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Introduction to COVID-19: methods for detection, prevention, response and control

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Coronaviruses are a large family of viruses that are known to cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS).

A novel coronavirus (COVID-19) was identified in 2019 in Wuhan, China. This is a new coronavirus that has not been previously identified in humans.

This course provides a general introduction to COVID-19 and emerging respiratory viruses and is intended for public health professionals, incident managers and personnel working for the United Nations, international organizations and NGOs.

As the official disease name was established after material creation, any mention of nCoV refers to COVID-19, the infectious disease caused by the most recently discovered coronavirus.

Please note that the content of this course is currently being revised to reflect the most recent guidance. You can find updated information on certain COVID-19-related topics in the following courses: Vaccination: COVID-19 vaccines channel IPC measures: IPC for COVID-19 Antigen rapid diagnostic testing: 1) SARS-CoV-2 antigen rapid diagnostic testing ; 2) Key considerations for SARS-CoV-2 antigen RDT implementation

Please note: These materials were last updated on 16/12/2020.

Course contents

Emerging respiratory viruses, including covid-19: introduction:, module 1: introduction to emerging respiratory viruses, including covid-19:, module 2: detecting emerging respiratory viruses, including covid-19: surveillance:, module 3: detecting emerging respiratory viruses, including covid-19: laboratory investigations:, module 4: risk communication :, module 5 : community engagement:, module 6: preventing and responding to an emerging respiratory virus, including covid-19:, enroll me for this course, certificate requirements.

• Gain a Record of Achievement by earning at least 80% of the maximum number of points from all graded assignments.
• Gain an Open Badge by completing the course.

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The Coronavirus: What Scientists Have Learned So Far

A respiratory virus that originated in China has infected more than 900,000 people worldwide, with at least 200,000 cases in the United States.

• Share full article

By Knvul Sheikh and Roni Caryn Rabin

A novel respiratory virus that originated in Wuhan, China , last December has spread to six continents . Hundreds of thousands have been infected, at least 20,000 people have died and the spread of the coronavirus was called a pandemic by the World Health Organization in March.

Much remains unknown about the virus, including how many people may have very mild or asymptomatic infections , and whether they can transmit the virus. The precise dimensions of the outbreak are hard to know.

Here’s what scientists have learned so far about the virus and the outbreak.

What is a coronavirus?

Coronaviruses are named for the spikes that protrude from their surfaces, resembling a crown or the sun’s corona. They can infect both animals and people, and can cause illnesses of the respiratory tract.

At least four types of coronaviruses cause very mild infections every year, like the common cold. Most people get infected with one or more of these viruses at some point in their lives.

Another coronavirus that circulated in China in 2003 caused a more dangerous condition known as Severe Acute Respiratory Syndrome, or SARS. The virus was contained after it had sickened 8,098 people and killed 774.

Coronavirus World Map: Tracking the Global Outbreak

The virus has infected and killed millions of people around the world. See detailed maps and charts for each country.

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• Patient Care & Health Information
• Diseases & Conditions
• Coronavirus disease 2019 (COVID-19)

COVID-19, also called coronavirus disease 2019, is an illness caused by a virus. The virus is called severe acute respiratory syndrome coronavirus 2, or more commonly, SARS-CoV-2. It started spreading at the end of 2019 and became a pandemic disease in 2020.

• Coronavirus

Coronaviruses are a family of viruses. These viruses cause illnesses such as the common cold, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and coronavirus disease 2019 (COVID-19).

The virus that causes COVID-19 spreads most commonly through the air in tiny droplets of fluid between people in close contact. Many people with COVID-19 have no symptoms or mild illness. But for older adults and people with certain medical conditions, COVID-19 can lead to the need for care in the hospital or death.

Staying up to date on your COVID-19 vaccine helps prevent serious illness, the need for hospital care due to COVID-19 and death from COVID-19 . Other ways that may help prevent the spread of this coronavirus includes good indoor air flow, physical distancing, wearing a mask in the right setting and good hygiene.

Medicine can limit the seriousness of the viral infection. Most people recover without long-term effects, but some people have symptoms that continue for months.

Typical COVID-19 symptoms often show up 2 to 14 days after contact with the virus.

Symptoms can include:

• Shortness of breath.
• Loss of taste or smell.
• Extreme tiredness, called fatigue.
• Digestive symptoms such as upset stomach, vomiting or loose stools, called diarrhea.
• Pain, such as headaches and body or muscle aches.
• Fever or chills.
• Cold-like symptoms such as congestion, runny nose or sore throat.

People may only have a few symptoms or none. People who have no symptoms but test positive for COVID-19 are called asymptomatic. For example, many children who test positive don't have symptoms of COVID-19 illness. People who go on to have symptoms are considered presymptomatic. Both groups can still spread COVID-19 to others.

Some people may have symptoms that get worse about 7 to 14 days after symptoms start.

Most people with COVID-19 have mild to moderate symptoms. But COVID-19 can cause serious medical complications and lead to death. Older adults or people who already have medical conditions are at greater risk of serious illness.

COVID-19 may be a mild, moderate, severe or critical illness.

• In broad terms, mild COVID-19 doesn't affect the ability of the lungs to get oxygen to the body.
• In moderate COVID-19 illness, the lungs also work properly but there are signs that the infection is deep in the lungs.
• Severe COVID-19 means that the lungs don't work correctly, and the person needs oxygen and other medical help in the hospital.
• Critical COVID-19 illness means the lung and breathing system, called the respiratory system, has failed and there is damage throughout the body.

Rarely, people who catch the coronavirus can develop a group of symptoms linked to inflamed organs or tissues. The illness is called multisystem inflammatory syndrome. When children have this illness, it is called multisystem inflammatory syndrome in children, shortened to MIS -C. In adults, the name is MIS -A.

When to see a doctor

Contact a healthcare professional if you test positive for COVID-19 . If you have symptoms and need to test for COVID-19 , or you've been exposed to someone with COVID-19 , a healthcare professional can help.

People who are at high risk of serious illness may get medicine to block the spread of the COVID-19 virus in the body. Or your healthcare team may plan regular checks to monitor your health.

Get emergency help right away for any of these symptoms:

• Can't catch your breath or have problems breathing.
• Skin, lips or nail beds that are pale, gray or blue.
• New confusion.
• Trouble staying awake or waking up.
• Chest pain or pressure that is constant.

This list doesn't include every emergency symptom. If you or a person you're taking care of has symptoms that worry you, get help. Let the healthcare team know about a positive test for COVID-19 or symptoms of the illness.

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COVID-19 is caused by infection with the severe acute respiratory syndrome coronavirus 2, also called SARS-CoV-2.

The coronavirus spreads mainly from person to person, even from someone who is infected but has no symptoms. When people with COVID-19 cough, sneeze, breathe, sing or talk, their breath may be infected with the COVID-19 virus.

The coronavirus carried by a person's breath can land directly on the face of a nearby person, after a sneeze or cough, for example. The droplets or particles the infected person breathes out could possibly be breathed in by other people if they are close together or in areas with low air flow. And a person may touch a surface that has respiratory droplets and then touch their face with hands that have the coronavirus on them.

It's possible to get COVID-19 more than once.

• Over time, the body's defense against the COVID-19 virus can fade.
• A person may be exposed to so much of the virus that it breaks through their immune defense.
• As a virus infects a group of people, the virus copies itself. During this process, the genetic code can randomly change in each copy. The changes are called mutations. If the coronavirus that causes COVID-19 changes in ways that make previous infections or vaccination less effective at preventing infection, people can get sick again.

The virus that causes COVID-19 can infect some pets. Cats, dogs, hamsters and ferrets have caught this coronavirus and had symptoms. It's rare for a person to get COVID-19 from a pet.

Risk factors

The main risk factors for COVID-19 are:

• If someone you live with has COVID-19 .
• If you spend time in places with poor air flow and a higher number of people when the virus is spreading.
• If you spend more than 30 minutes in close contact with someone who has COVID-19 .

Many factors affect your risk of catching the virus that causes COVID-19 . How long you are in contact, if the space has good air flow and your activities all affect the risk. Also, if you or others wear masks, if someone has COVID-19 symptoms and how close you are affects your risk. Close contact includes sitting and talking next to one another, for example, or sharing a car or bedroom.

It seems to be rare for people to catch the virus that causes COVID-19 from an infected surface. While the virus is shed in waste, called stool, COVID-19 infection from places such as a public bathroom is not common.

Serious COVID-19 illness risk factors

Some people are at a higher risk of serious COVID-19 illness than others. This includes people age 65 and older as well as babies younger than 6 months. Those age groups have the highest risk of needing hospital care for COVID-19 .

Not every risk factor for serious COVID-19 illness is known. People of all ages who have no other medical issues have needed hospital care for COVID-19 .

Known risk factors for serious illness include people who have not gotten a COVID-19 vaccine. Serious illness also is a higher risk for people who have:

• Sickle cell disease or thalassemia.
• Serious heart diseases and possibly high blood pressure.
• Chronic kidney, liver or lung diseases.

People with dementia or Alzheimer's also are at higher risk, as are people with brain and nervous system conditions such as stroke. Smoking increases the risk of serious COVID-19 illness. And people with a body mass index in the overweight category or obese category may have a higher risk as well.

Other medical conditions that may raise the risk of serious illness from COVID-19 include:

• Cancer or a history of cancer.
• Type 1 or type 2 diabetes.
• Weakened immune system from solid organ transplants or bone marrow transplants, some medicines, or HIV .

This list is not complete. Factors linked to a health issue may raise the risk of serious COVID-19 illness too. Examples are a medical condition where people live in a group home, or lack of access to medical care. Also, people with more than one health issue, or people of older age who also have health issues have a higher chance of severe illness.

Related information

• COVID-19: Who's at higher risk of serious symptoms? - Related information COVID-19: Who's at higher risk of serious symptoms?

Complications

Complications of COVID-19 include long-term loss of taste and smell, skin rashes, and sores. The illness can cause trouble breathing or pneumonia. Medical issues a person already manages may get worse.

Complications of severe COVID-19 illness can include:

• Acute respiratory distress syndrome, when the body's organs do not get enough oxygen.
• Shock caused by the infection or heart problems.
• Overreaction of the immune system, called the inflammatory response.
• Blood clots.
• Kidney injury.

Post-COVID-19 syndrome

After a COVID-19 infection, some people report that symptoms continue for months, or they develop new symptoms. This syndrome has often been called long COVID, or post- COVID-19 . You might hear it called long haul COVID-19 , post-COVID conditions or PASC. That's short for post-acute sequelae of SARS -CoV-2.

Other infections, such as the flu and polio, can lead to long-term illness. But the virus that causes COVID-19 has only been studied since it began to spread in 2019. So, research into the specific effects of long-term COVID-19 symptoms continues.

Researchers do think that post- COVID-19 syndrome can happen after an illness of any severity.

Getting a COVID-19 vaccine may help prevent post- COVID-19 syndrome.

The Centers for Disease Control and Prevention (CDC) recommends a COVID-19 vaccine for everyone age 6 months and older. The COVID-19 vaccine can lower the risk of death or serious illness caused by COVID-19.

The COVID-19 vaccines available in the United States are:

2023-2024 Pfizer-BioNTech COVID-19 vaccine. This vaccine is available for people age 6 months and older.

Among people with a typical immune system:

• Children age 6 months up to age 4 years are up to date after three doses of a Pfizer-BioNTech COVID-19 vaccine.
• People age 5 and older are up to date after one Pfizer-BioNTech COVID-19 vaccine.
• For people who have not had a 2023-2024 COVID-19 vaccination, the CDC recommends getting an additional shot of that updated vaccine.

2023-2024 Moderna COVID-19 vaccine. This vaccine is available for people age 6 months and older.

• Children ages 6 months up to age 4 are up to date if they've had two doses of a Moderna COVID-19 vaccine.
• People age 5 and older are up to date with one Moderna COVID-19 vaccine.

2023-2024 Novavax COVID-19 vaccine. This vaccine is available for people age 12 years and older.

• People age 12 years and older are up to date if they've had two doses of a Novavax COVID-19 vaccine.

In general, people age 5 and older with typical immune systems can get any vaccine approved or authorized for their age. They usually don't need to get the same vaccine each time.

Some people should get all their vaccine doses from the same vaccine maker, including:

• Children ages 6 months to 4 years.
• People age 5 years and older with weakened immune systems.
• People age 12 and older who have had one shot of the Novavax vaccine should get the second Novavax shot in the two-dose series.

Talk to your healthcare professional if you have any questions about the vaccines for you or your child. Your healthcare team can help you if:

• The vaccine you or your child got earlier isn't available.
• You don't know which vaccine you or your child received.
• You or your child started a vaccine series but couldn't finish it due to side effects.

People with weakened immune systems

Your healthcare team may suggest added doses of COVID-19 vaccine if you have a moderately or seriously weakened immune system. The FDA has also authorized the monoclonal antibody pemivibart (Pemgarda) to prevent COVID-19 in some people with weakened immune systems.

Control the spread of infection

In addition to vaccination, there are other ways to stop the spread of the virus that causes COVID-19 .

If you are at a higher risk of serious illness, talk to your healthcare professional about how best to protect yourself. Know what to do if you get sick so you can quickly start treatment.

If you feel ill or have COVID-19 , stay home and away from others, including pets, if possible. Avoid sharing household items such as dishes or towels if you're sick.

In general, make it a habit to:

• Test for COVID-19 . If you have symptoms of COVID-19 test for the infection. Or test five days after you came in contact with the virus.
• Help from afar. Avoid close contact with anyone who is sick or has symptoms, if possible.
• Wash your hands. Wash your hands well and often with soap and water for at least 20 seconds. Or use an alcohol-based hand sanitizer with at least 60% alcohol.
• Cover your coughs and sneezes. Cough or sneeze into a tissue or your elbow. Then wash your hands.
• Clean and disinfect high-touch surfaces. For example, clean doorknobs, light switches, electronics and counters regularly.

Try to spread out in crowded public areas, especially in places with poor airflow. This is important if you have a higher risk of serious illness.

The CDC recommends that people wear a mask in indoor public spaces if you're in an area with a high number of people with COVID-19 in the hospital. They suggest wearing the most protective mask possible that you'll wear regularly, that fits well and is comfortable.

• COVID-19 vaccines: Get the facts - Related information COVID-19 vaccines: Get the facts
• Comparing the differences between COVID-19 vaccines - Related information Comparing the differences between COVID-19 vaccines
• Different types of COVID-19 vaccines: How they work - Related information Different types of COVID-19 vaccines: How they work
• Debunking COVID-19 myths - Related information Debunking COVID-19 myths

Travel and COVID-19

Travel brings people together from areas where illnesses may be at higher levels. Masks can help slow the spread of respiratory diseases in general, including COVID-19 . Masks help the most in places with low air flow and where you are in close contact with other people. Also, masks can help if the places you travel to or through have a high level of illness.

Masking is especially important if you or a companion have a high risk of serious illness from COVID-19 .

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• Published: 17 May 2022

Immune response in COVID-19: what is next?

• Qing Li   ORCID: orcid.org/0000-0003-1990-5857 1   na1 ,
• Ying Wang   ORCID: orcid.org/0000-0002-2571-9367 2   na1 ,
• Qiang Sun 3   na1 ,
• Jasmin Knopf   ORCID: orcid.org/0000-0003-2922-9370 4 , 5 ,
• Martin Herrmann   ORCID: orcid.org/0000-0002-0258-2484 4 , 5 ,
• Liangyu Lin   ORCID: orcid.org/0000-0003-4312-8955 2 ,
• Jingting Jiang   ORCID: orcid.org/0000-0002-3128-9762 1 ,
• Changshun Shao   ORCID: orcid.org/0000-0003-2618-9342 1 ,
• Peishan Li   ORCID: orcid.org/0000-0002-6881-396X 1 ,
• Xiaozhou He 1 ,
• Fei Hua 1 ,
• Zubiao Niu 3 ,
• Chaobing Ma 3 ,
• Yichao Zhu 3 ,
• Giuseppe Ippolito 6 ,
• Mauro Piacentini 7 ,
• Jerome Estaquier   ORCID: orcid.org/0000-0002-9432-8044 8 , 9 ,
• Sonia Melino 7 ,
• Felix Daniel Weiss   ORCID: orcid.org/0000-0003-0228-5081 10 ,
• Emanuele Andreano   ORCID: orcid.org/0000-0003-0088-5788 11 ,
• Eicke Latz   ORCID: orcid.org/0000-0003-1488-5666 10 , 12 ,
• Joachim L. Schultze   ORCID: orcid.org/0000-0003-2812-9853 12 , 13 ,
• Rino Rappuoli 11 ,
• Alberto Mantovani   ORCID: orcid.org/0000-0001-5578-236X 14 , 15 , 16 ,
• Tak Wah Mak 17 , 18 ,
• Gerry Melino   ORCID: orcid.org/0000-0001-9428-5972 12 , 19 &
• Yufang Shi   ORCID: orcid.org/0000-0001-8964-319X 1 , 2 , 19  

Cell Death & Differentiation volume  29 ,  pages 1107–1122 ( 2022 ) Cite this article

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• Antimicrobial responses
• Infectious diseases

The coronavirus disease 2019 (COVID-19) has been a global pandemic for more than 2 years and it still impacts our daily lifestyle and quality in unprecedented ways. A better understanding of immunity and its regulation in response to SARS-CoV-2 infection is urgently needed. Based on the current literature, we review here the various virus mutations and the evolving disease manifestations along with the alterations of immune responses with specific focuses on the innate immune response, neutrophil extracellular traps, humoral immunity, and cellular immunity. Different types of vaccines were compared and analyzed based on their unique properties to elicit specific immunity. Various therapeutic strategies such as antibody, anti-viral medications and inflammation control were discussed. We predict that with the available and continuously emerging new technologies, more powerful vaccines and administration schedules, more effective medications and better public health measures, the COVID-19 pandemic will be under control in the near future.

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Open Questions

How to determine the importance of specific CD8 + T cells in the immunity to SARS-CoV-2?

How will the COVID-19 pandemic end? Will COVID-19 become endemic?

How will the Omicron variant evolve? What immune properties will the next variant have?

Will herd immunity built up by vaccination and natural infections end the transmission of SARS-CoV-2 virus?

Pandemic infectious diseases have wreaked havoc on human society multiple times, including the times of the “Plague of Athens” (over 100,000 deaths in 430 BC), Yersinia pestis (50 million deaths in 1340) or “Spanish influenza” (50 million deaths in 1918). These also include several viral diseases like HIV (40 million deaths in 1980–2000), H1N1 “Swine flu” (300,000 deaths in 2009), yellow fever, Zika, Ebola, SARS, MERS, and the current coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Despite that more than two years have passed since the first appearance of COVID-19, the lifestyle, economic activities, and social behaviors of our world are still being impacted by this pandemic [ 1 ]. With over 500 million confirmed COVID-19 cases (over 6% of the world population) and circa 6.5 million deaths worldwide, the causing virus, SARS-CoV-2 [ 2 , 3 , 4 , 5 , 6 ], shows a rapidly expanding genealogy to now warranting a classification for at least 13 variants and appears to become endemic, with mutations at the N-terminus and the receptor-binding region, including p.Glu484Lys found in the most dangerous variants [ 7 ], Fig.  1 . The variants of concern (VoC) have been Alpha, Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529), with Delta and Omicron being the most alarming ones [ 8 ]. Dreadfully, a new variant with the Delta backbone and Omicron spike has emerged [ 9 ]. Great progress has been made in controlling the COVID-19 pandemic, however, much of the efforts still focus on reducing infection and disease severity by vaccination (more than 11 billion vaccine doses administered) [ 10 , 11 , 12 ], which occasionally caused some adverse effects [ 13 ]. In the meantime, the virus tends to evolve into variants with high transmission and low pathogenicity [ 14 ]. Unfortunately, it is almost certain that the virus will gain new mutations, possibly with higher pathogenicity.

The top panel shows the mutation profiling and prevalence of spike proteins across 13 SARS-CoV-2 lineages that received a Greek designation and 7 recently emerged SARS-CoV-2 variants with public attention. The parent lineages of the new SARS-CoV-2 variants were depicted in the table. The bottom images show the side and top view of the 3-dimension structure for the Omicron spike protein with mutation amino acids mapped [ 170 ]. Note: the insertion mutations are not profiled.

Here, we review the yin and yang of innate and adaptive immunity of acute SARS-CoV-2 infection and emphasize open outstanding questions.

Underlying inflammatory conditions and infection severity

The majority of people infected with SARS-CoV-2 experience mild to moderate respiratory illness, including fever, cough, shortness of breath, muscle aches, headache, loss of taste and smell, sore throat, congestion, or runny nose; while some become seriously ill and require medical attention, especially the elderly and those with underlying medical conditions such as cardiovascular disease, diabetes, chronic respiratory disease, or cancer [ 15 ]. Clearly, the inflammatory conditions, as well as the immune status of patients, are critical in determining the course of the disease progression [ 12 ].

The deceased among COVID-19 patients exhibited a strong association with age [ 1 ]. The group at 30 or younger had fewer mortalities, while the group at 65 or older showed dramatically high mortality (Data.CDC.gov). In most countries, more death was observed in infected men than in infected women [ 16 ]. A higher COVID-19 death rate was also observed in smokers, obese individuals, and patients suffering from chronic kidney disease, cardiovascular disease, or cancer [ 17 ]. The biggest change in the death rate is associated with the recent appearance of the Omicron variant, which is highly transmissible with a death rate lower than other VoC [ 18 , 19 ]. Of course, this alteration in the death rate could be due to the success of vaccination. Indeed, it has been reported that among the unvaccinated, especially those over 75-year-old, the mortality is still very significant [ 20 ].

As flying mammals, bats are a super zodiac reservoir of viruses, especially coronaviruses. However, bats have a unique immune system that is well balanced between defense and immune tolerance, which prevents them from developing pathological changes after viral infection. They have enhanced constitutive expression of Interferons (IFNs), interferon-stimulated genes, and several heat-shock proteins. On the other hand, bats have reduced stimulator of interferon genes (STING) and suppressed NLR family pyrin domain containing 3 (NLRP3) inflammasome [ 21 ]. On contrary to bats, humans are not completely resistant to some coronavirus infection [ 21 ]. It is interesting to note that unlike infections with other viruses such as smallpox, measle, or rabies, exposure to SARS-CoV-2, especially with the Omicron variant, of individuals who received a vaccine or recovered from a prior infection with other variants, could result in disease, yet with milder or no symptoms [ 22 ]. Such evasion of the immune system makes the elimination of the virus more difficult. Genetic variation in the SARS-CoV-2 virus is certainly a major contributing factor to incomplete immune protection. Most work until now strongly supported the notion that SARS-CoV-2 does not infect circulating blood leukocytes, since they do not express the SARS-CoV-2 receptor, the angiotensin-converting enzyme 2 (ACE2). A very recent study [ 23 ] suggested that up to 6% of blood monocytes can be infected with the virus, however, this requires further confirmation. Another important factor is that the mucosal SARS-CoV-2 specific IgM and IgA decay very fast [ 24 ]. It is also possible that virus neutralization could only be achieved by the receptor-binding domain (RBD)-specific antibodies and that the RBD is hidden by protein folding until right before binding to ACE2 [ 25 ].

Innate immunity

Numerous studies throughout the last two years have established the innate immune system as a critical defender against SARS-CoV-2. In the best cases, innate immunity eliminates SARS-CoV-2 without activation of the adaptive immune system, thus creating a so-called “never-COVID” cohort. This notion is strongly supported by a recently launched human SARS-CoV-2 challenge study (NCT04865237), in which 36 young health volunteers were intranasally administrated with 10 TCID50 of SARS-CoV-2/human/GBR/484861/2020 (a D614G containing pre-alpha wild-type virus; Genbank accession number OM294022). Surprisingly, 16 volunteers (~44.4%) remained uninfected upon the deliberate SARS-CoV-2 exposure. Their C-reactive protein (CRP), SARS-CoV-2 neutralizing antibody, and spike-specific IgG remain negative, excluding the contributions of adaptive immune cells in such protections [ 26 ]. However, the innate immune defenders can also become deleterious when inappropriately activated during SARS-CoV-2 infections [ 27 ].

Cellular innate immunity

Genetic evidence indicates that cell-mediated innate immunity plays a key role in resistance to COVID-19 and in the pathogenesis of severe disease [ 28 , 29 , 30 ]. Genes emerging as playing a key role include chemokines and their cognate receptors and members of the IFN pathway. Cellular and innate immune receptors recognizing SARS-CoV-2 belong to different classes [ 31 ]. Mouse and human genetic data unequivocally prove that GU-rich RNA sequences are recognized by Toll-like receptor 7 (TLR7) in plasmacytoid dendritic cells (pDC) and TLR8 in conventional DC and myeloid cells [ 32 ]. These TLR receptors are located in the endosomal compartment and trigger IFN production (pDC), antigen presentation and uncontrolled inflammation at later stages. Consistent with these in vitro and in vivo mouse data, TLR7 genetic deficiency was associated with severe disease [ 33 ]. Cytosolic receptors including the retinoic acid-inducible gene-1 (RIG-1) complex have also been suggested to sense SARS-CoV-2 nucleic acids [ 31 ]. Finally, recent evidence suggests that surface C-type lectins interact with the glycosidic components of spike and play an important role in viral entry [ 34 , 35 , 36 , 37 ].

Pro-inflammatory macrophages are the major immune cell type that expresses high levels of ACE2 [ 38 ]. Upon SARS-CoV-2 infection, these macrophages release inflammatory cytokines and chemokines including C-C motif chemokine ligand 7 (CCL7), CCL8 and CCL13 to recruit and activate T cells. In turn, T cells produce IFN-γ and other cytokines to further activate macrophages [ 39 ]. This positive feedback loop drives the elevation and continuation of the pathological inflammation. Epidemiological data show that older adults and people with underlying health conditions exhibited a dramatically high rate of severe disease and mortality [ 17 ]. Along with aging, there is a tendency of increasing inflammatory macrophages [ 40 ]. This not only explains why chronic inflammatory disease occurrence is more prevalent but also provides a possibility accounting for the high incidence of severe COVID-19 cases in older people. Along with this scenario, it is reasonable to comprehend why SARS-CoV-2 infection in those with underlying medical conditions also exhibited a higher prevalence in severe disease and mortality [ 12 ].

Single-cell sequencing in combination with cytometry by time of flight (CyTOF), Cite-Sequencing, or multi-color flow cytometry has been particularly informative to describe the deviations of innate immune cells in COVID-19 patients. Early on it was demonstrated that granulocytes and monocytes were dramatically altered in patients with severe disease courses, while moderate and mild disease courses showed rather regular inflammatory cell activation programs with high level human leukocyte antigen-DR (HLA-DR) and CD11c expression [ 27 ]. In severe COVID-19, monocytes are characterized by high level expression of alarmins and CD163, while major histocompatibility complex (MHC) molecules are reduced. Within the neutrophil compartment, cell states reminiscent of myeloid-derived suppressor like cells are observed in severe COVID-19 and at the same time cellular programs necessary for neutrophil extracellular traps (NET)-formation are overexpressed. Further, the appearance of neutrophil precursors in the blood is evident for emergency myelopoiesis in patients with severe COVID-19. Mononuclear phagocytes are extremely plastic and diverse and undergo different forms of activation and tolerance [ 41 , 42 ]. Macrophages’ function has an adaptive component which has been referred to as “training”. Trained innate immunity underlies pathogen agnostic protection associated with selected vaccines, infections and cytokines such as interleukin-1 (IL-1) [ 43 ]. There is evidence that trained innate immunity can contribute to resistance against COVID-19. For instance, if mothers were indirectly exposed to live polio vaccine because of vaccination, their babies were found to have decreased symptomatic infection with COVID-19 [ 44 ]. The relevance of trained innate immunity to COVID-19 and to vaccines in current use remains to be defined.

A major clinical problem of severe COVID-19 is the development of an “acute respiratory distress syndrome” (ARDS) associated with prolonged respiratory failure and high mortality. Also, here innate immune cells are related to this pathophysiological reaction in severe COVID-19 [ 45 ]. In ARDS patients, CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype accumulate [ 45 ]. The profibrotic programs of lung macrophages in COVID-19 are reminiscent of cellular reprogramming previously identified in idiopathic pulmonary fibrosis. Strikingly, the in vitro exposure of monocytes to SARS-CoV-2 sufficiently induced such a profibrotic phenotype [ 45 ].

Other innate immune cells are also altered in COVID-19 [ 46 ]. For example, in severe COVID-19 patients, Nature killer (NK) cells showed a prolonged expression of IFN-stimulated genes (ISGs), while tumor necrosis factor (TNF)-induced genes were observed in mild and moderate disease. Further, NK cells in severe COVID-19 showed impaired function against SARS-CoV-2 infected cells and impaired anti-fibrotic activity [ 46 ]. Other studies suggested that untimely transforming growth factor β (TFGβ) responses limit the antiviral functions of NK cells in severe disease [ 47 ]. Surprisingly, other blood-derived cells including megakaryocytes, and erythroid cells were also characterized by an increased expression of ISGs in severe but not mild COVID-19 further supporting prolonged IFN response being directly related to disease severity [ 48 ].

Further, SARS-CoV-2 seems to trigger an innate functionality in a subset of T cells, namely highly activated CD16 + T cells, which occur mainly in severe COVID-19 in the CD4, CD8 and γδ T cell compartments [ 49 ]. It was demonstrated that increased generation of C3a in severe COVID-19 induced this peculiar T cell phenotype. Functionally, CD16 enabled immune-complex-mediated, T cell receptor (TCR)-independent degranulation and cytotoxicity, which so far, seems to be specific to SARS-CoV-2. These functions were further linked to the release of neutrophil and monocyte chemoattractants and microvascular endothelial cell injury, the latter being made responsible for the heterogeneous and manifold clinical symptoms involving many different organs in severe COVID-19. Worrisome is the persistence of the cytotoxic phenotype of CD16 + T cell clones beyond acute disease which might also be involved in pathophysiological mechanisms associated with long COVID. However, this clearly requires further investigation. Innate functionality of CD16 + T cells not only seems to play an important pathophysiological role, but the proportion of these cells together with plasma levels of complement proteins upstream of C3a were shown to be associated with fatal outcomes.

Humoral innate immune response to SARS-CoV-2 infection

Innate immunity consists of a cellular and a humoral arm [ 50 ]. Components of the humoral arm of innate immunity are a diverse set of molecules, such as Complement components, collectins (e.g., Mannose-binding lectin, MBL), ficolins, and pentraxins (e.g., C reactive protein, CRP, and PTX3) [ 50 , 51 ]. These fluid phase pattern recognition molecules have functions similar to antibodies (ante-antibodies). Among these ante-antibodies, MBL was found to bind spike by recognizing its glycosidic moieties and to inhibit SARS-CoV-2 [ 36 ]. All VoCs including Omicron were recognized by MBL. MBL haplotypes were found to be associated with disease severity [ 36 ]. Pentraxin 3 (PTX3), but not its distant relative CRP bound the SARS-CoV-2 nucleoprotein, but it remains to be elucidated whether its recognition amplifies inflammation [ 36 ]. Indeed, PTX3 has emerged as an important biomarker of disease severity with for instance death as the endpoint [ 52 , 53 , 54 , 55 , 56 ]. The results have been extended to long COVID [ 57 ] with PTX3 being part of a disease severity signature.

Complement has emerged as a pathway of amplification of inflammation and tissue damage [ 58 ]. The lectin pathway may play a role in complement activation. Small pilot studies suggest that targeting complement by inhibiting the C3 convertase or by blocking mannose-associated serine protease (MASP) and the lectin pathway may be beneficial in COVID-19 [ 49 , 59 , 60 , 61 , 62 , 63 ]. Whether these therapeutic approaches might also impact the functionality of the highly activated CD16 + T cells with innate immune function requires further investigation [ 49 ].

Thus, humoral innate immunity (ante-antibodies) plays an important role in COVID-19. MBL represents a non-redundant pathway of resistance against SARS-CoV-2 VoC. The pentraxins CRP and PTX3 provide important prognostic indicators, with PTX3 integrating myeloid cell and endothelial cell activation. It will be important to further explore the value and significance of ante-antibodies as biomarkers (PTX3), candidate therapeutics (MBL) and therapeutic targets (complement).

Macrophages and monocytes express a variety of pattern recognition receptors (PRRs), including TLRs, (NOD)-like receptor family proteins (NLRs), absent in melanoma 2 (AIM2) and the cyclic GMP-AMP synthase (cGAS)-STING pathway. These can trigger innate immune responses to viral infection through direct infection and sensing of SARS-CoV-2 or by detecting damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) released by infected cells that act as a feedforward mechanism propagating the systemic inflammatory response.

Single-cell sequencing and flow cytometric analyses have established the presence of SARS-CoV-2 RNA in human lung macrophages [ 30 , 39 ] and blood monocytes [ 64 ]. Neither human lung macrophages nor monocytes express the primary SARS-CoV-2 internalization receptor ACE2, and as such alternative mechanisms for viral internalization have been proposed, including Fc-receptor mediated uptake [ 23 , 65 ]. Lung myeloid cells infected with SARS-CoV-2 induce the transcriptional programs and signaling cascades of innate immune response. SARS-CoV-2-infected cells upregulate chemokines, cytokines, IFN pathway and TNF associated genes [ 30 , 39 ]. These act to inhibit viral expansion and recruit monocytes and T cells to the site of infection. However, excessive release of pro-inflammatory cytokines was early identified in severe COVID-19 patients [ 66 ]. The detection of viral RNA potentially drives activation of this transcriptional response by endosomal TLR3 and TLR7, as well as SARS-CoV-2 E protein detection on the cell membrane by TLR2 [ 67 ].

Recent reports have shown the presence of an oligomerized apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain (CARD) alongside NLRP3 in monocytes and lung macrophages from COVID-19 patients [ 68 ]. The monocytes displayed a concomitant activation of caspase-1, and cleavage and translocation of the gasdermin D pore complex to the plasma membrane, a downstream event of inflammasome activation that facilitates cytokine release and precedes the inflammatory lytic cell death process known as pyroptosis. Indeed, sera from COVID-19 patients are enriched for IL-1β, IL-18 and lactate dehydrogenase (LDH), indicative of ongoing pyroptosis [ 68 ]. In the lungs of COVID-19 individuals, inflammasome activation is not exclusive to SARS-CoV-2-infected cells, suggesting that paracrine signals caused by SARS-CoV-2 infection can induce pyroptosis in neighboring cells, potentiating the inflammatory response and disease severity [ 64 ].

Inhibitors targeting inflammasome pathway components, including caspase-1 and NLRP3 reduced pathology in a humanized mouse model of SARS-CoV-2 infection [ 65 ], suggesting therapeutic targeting of the NLRP3 inflammasome may provide translational benefit as society proceeds to live alongside SARS-CoV-2. However, it is important to bear in mind that most studies on human patients rely on post-mortem tissues and therefore represent the most severe form of the disease. Consequently, it remains to be seen whether inflammasome inhibition can yield effective results in mild forms of COVID-19.

The innate immune response to SARS-CoV-2 infection is not limited to macrophages and monocytes, and is frequently associated with abnormal activation and recruitment of neutrophils. It has been reported that there is a dramatic increase in myeloid-derived suppressor-like cells (MDSC-like) [ 69 ], particularly in those at severe stages of COVID-19, contributing to the pathogenesis of SARS-CoV-2 infection. MDSCs may delay the clearance of the SARS-CoV-2 virus and inhibit T cell proliferation and functions. Neutrophils are known to release NET and the imbalance between NET formation and degradation plays a central role in the pathophysiology through trapping inflammatory cells and preventing the recruitment of tissue repairing cells. Strategies that dysregulate the formation of NET or destruct NET with agents such as DNase could represent new therapies for COVID-19 patients, especially those suffering from severe illness [ 2 ], see below.

NET-driven vascular occlusions drive pathology in severe COVID-19

During the membrane rupture of granulocytes in the process of NET formation the preformed pro-inflammatory cytokines (e.g., IL-6) and chemokines (e.g., IL-8, CCL3) as well as antimicrobial peptides (e.g., bactericidal/permeability-increasing protein and histones), serine proteases (e.g., neutrophil elastase and proteinase 3), other enzymes (e.g., myeloperoxidase, lactoferrin, lysozyme and phospholipase A2), and reactive oxygen species (ROS) are released into the vicinity of NET. The activity of the soluble mediators fades as NET formed in high neutrophil densities tends to aggregate. These aggregates act anti-inflammatorily as NET-borne proteases proteolytically degrade inflammatory mediators and toxic histones [ 70 , 71 ]. Importantly, DNA-bound proteases are not antagonized by anti-proteases [ 72 ]. Thus, the formation of NET is considered a double-edged sword that initially initiates inflammation and later helps to orchestrate its resolution.

The imbalance between NET formation and degradation can also drive inflammation, e.g., by occluding vessels and ducts [ 73 ]. First reports about the role of NET in patients with COVID-19 were already published soon after the onset of the pandemic describing elevated levels of NET markers such as cell-free DNA, citrullinated Histone H3 (citH3), and myeloperoxidase-DNA (MPO-DNA) complexes in the sera of these patients [ 74 ]. Single cell sequencing of blood-derived neutrophils from peripheral blood supported a reprogramming of a subset of neutrophils towards NET formation-related transcriptional programs especially in severe COVID-19 [ 27 ]. Serum from patients with COVID-19 as well as the virus itself were reportedly able to trigger NET formation accompanied by increasing levels of intracellular ROS [ 74 , 75 , 76 ]. This ROS-NET pathway together with the activation of neutrophils, the formation of neutrophil-platelet aggregates, and intravascular aggregation of NET enriched with complement and tissue factors form occlusive NET-derived immunothromboses, Fig.  2 . This is particularly dangerous in the microvasculature, where severe organ damage occurs due to disrupted microcirculation [ 72 , 77 , 78 , 79 ]. Because of their central role in the pathophysiology of COVID-19, NET is a prime target for therapeutical intervention. Therapeutic doses of heparin were shown to prevent the aggregation of NET by nano- and microparticles and the efficiency of this therapy in COVID-19 patients was shown recently [ 80 , 81 ]. Furthermore, Heparin is known to accelerate the DNase I-mediated degradation of NET and first trials with Dornase Alfa, a recombinant DNase, have been undertaken [ 82 , 83 ]. Disulfiram was also reportedly successful in the reduction of NET, increase of survival, and improvement of blood oxygenation in animal models, which makes it a new promising candidate for the treatment of NET-related pathologies in patients with COVID-19 [ 84 ]. Lastly, inhibitors of peptidyl-arginine deiminases (PADs) are discussed as therapies to treat NET-related thrombotic complications in patients with COVID-19, however, no clinical trial has been conducted yet [ 85 ].

Immune fluorescence detects the NET components citrullinated Histone H3 and neutrophil elastase (both green) as well as extranuclear DNA (DAPI; red) in the vessels of a central human lung. Note, the intravascular DNA-enzyme-histone complexes fill the whole lumen of many vessels (some of the clogged vessels are marked with asterisks).

Targeting the type I IFN production by SARS-CoV-2

While innate immunity constitutes the first line of host defense against virus infection, the type-I IFN response is the core that endows antiviral activities to host cells, which consists of two major consecutive steps including IFN production and the expression of ISGs [ 86 ]. Here, we specifically focus on the regulation of type-I IFN production, which is the first and critical step for an effective innate immune response and therefore is primarily targeted by SARS-CoV-2 proteins for suppression.

As depicted in Fig.  3 , the type-I interferon production is initiated by the recognition of the double-strand RNA (dsRNA) generated during the virus life cycle by the RIG-1-like receptors (RLRs), including the RIG-1 and/or melanoma differentiation gene 5 (MDA5) in the cytoplasm, or the TLRs in the endosome [ 87 ]. Upon loading with dsRNA, RIG-1 and MDA5 can interact with the adapter mitochondrial antiviral signaling protein (MAVS), leading to the formation of a signaling complex consisting of TANK-binding kinase 1 (TBK1) and inducible IκB kinase (IKKi). The TBK1/IKKi complex then phosphorylates interferon regulatory factor 3/7 (IRF3/7), promoting their translocation into the nucleus to drive IFN-α/β expression. Meanwhile, the TLRs, such as TLR3, could also recognize PAMPs in the endosome to induce cytokines and chemokines production, enhancing the innate immune response [ 87 ].

a Schematic demonstration of the viral proteins. Those marked with asterisks were reported to regulate IFN production. b IFN production signaling pathways targeted by SARS-CoV-2 proteins. SARS-CoV-2 infection induces a delayed type-I IFN response, which is underlaid by the inhibited RIG-I/MDAS-MAVS signaling at the early stage and the cytoplasmic-micronuclei-activated cGAS-STING signaling at the late stage.

During this process, it was reported that SARS-CoV-2 encoded at least 14 proteins, accounting for about half of the total proteins encoded by the virus, to interfere with IFN production [ 88 , 89 , 90 ]. These proteins include the structural membrane (M), nucleocapsid (N) proteins, the accessory proteins (3, 6, 8, and 9b), and the nonstructural proteins (NSP1, 3, 5, 6, 12,13, 14, and 15) generated from a large open reading frame (ORF) encoding 1ab by papain-like proteinase (NSP3, NLpro) and 3C-like proteinase (NSP5, 3CLpro) -mediated cleavage. Suppression of IFN production by the SARS-CoV-2 proteins was primarily executed through four types of mechanisms, including escaping viral RNA recognition (by N, ORF9b, NSP1, and NLpro), compromising RIG-1 or TLRs signaling (by M, N, 3CLpro, NSP12, ORF3b, ORF6, ORF7b, and ORF9b), targeting the TBK1 complex (by M, N, NSP13, ORF9b,), and interfering with IRF3 activation (by M, N, NLpro, 3CLpro, NSP1, NSP12–15, ORF3b, ORF6, and ORF8), Fig.  3 . Corresponding to the extensive interference of IFN production by SARS-CoV-2-encoded proteins, patients with COVID-19 usually exhibited a delayed type-I IFN response [ 90 ], i.e., IFN production was inhibited at the early stage of SARS-CoV-2 infection, which allows the virus to achieve successful replication in the host cells, undermining the asymptomatic infection. Enhancing IFN response at this stage turned out to help restrict SARS-CoV-2 infection [ 91 , 92 , 93 ].

Subsequent to a latent IFN response, the patients with COVID-19, particularly those in severe forms, exhibited a substantially exaggerated IFN response manifested with uncontrolled cytokine storm and inflammation, corresponding to another arm of the delayed type-I IFN response at the late stage [ 90 ], on which recent studies shed lights. Zhao et al. reported that an expression level-based dual-role of the structural N protein may be partially accountable, where the low-dose N protein was suppressive while the high-dose was promotive, for the activation of IFN signaling. This worked out by dually regulating the phosphorylation and nuclear translocation of IRF3 [ 94 ]. Alternatively, Ren et al. found that SARS-CoV-2 may activate IFN response unexpectedly via the cGAS-STING signaling pathway, which was induced by the cytoplasmic micronuclei produced in the multinucleate syncytia between cells expressing spike and ACE2 [ 95 ]. And the results were further confirmed independently by Zhou et al., who demonstrated that cell-cell fusion was sufficient to induce cytoplasmic chromatin, and the cytoplasmic chromatin-cGAS-STING pathway, but not the MAVS-mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion [ 96 ]. Interestingly, several SARS-CoV-2 proteins (3CLpro, ORF3a, and ORF9) were also able to target STING to regulate the IFN response [ 97 ], likely indicating a complex feedback interaction between SARS-CoV-2 and the innate immunity, and therefore a well-balanced immune interference targeting IFN response is required for COVID-19 therapy.

Adaptive immunity: humoral immunity to SARS-CoV-2

Adaptive immunity provides pathogen-specific immunity, which eradicates infection and provides long memory and recall of the immune responses, Fig.  4 . By producing antibodies, B cells play a critical role in anti-viral immunity. Different classes of antibodies such as IgM, IgA, IgG, and IgE, are involved in humoral immune responses to viral infections. These antibody classes are characterized by their intrinsic properties, functions, tissue distributions, and half-lives. Upon SARS-CoV-2 infection or vaccination, IgD and IgM are the first antibody types produced. The positive test of IgM antibody indicates that the virus may be present or a patient recently recovered from the infection and that the virus-specific immune response has begun [ 98 ]. During SARS-CoV-2 infection, symptoms start around day 5 and the body begins to produce IgM antibodies around 7–8 days post-infection [ 99 ]. Due to inadequate affinity maturation, IgM antibodies have a relatively low affinity compared to IgG. On the other hand, due to their pentameric nature, IgM antibodies have high avidity for antigens and play critical roles in opsonization.

In a typical SARS-CoV-2 infection, the virus presented in the lymphoid organs evokes T helper cells which facilitate the activation of both humoral and cellular immune responses. Antibodies and effector CD8 + T cells were then released into circulation. Antibodies neutralize virus and eliminate infected cells through ADCC. CD8 + T cells kill infected cells through cytotoxicity. However, as for SARS-CoV-2 Omicron, the effects of antibody-mediated protection were dramatically reduced, which is possibly brought about by over 30 mutations in the genes encoding spike proteins. There are 3 possibilities explaining the sudden appearance of Omicron: 1. Omicron may have been transmitted within a neglected population without sufficient medical surveillance; 2. It could be outcompeted in a patient with chronic COVID-19 infections; 3. It may be zoonotic and just spilled back into human.

IgG antibodies usually appear later during an immune response because of the time needed for their affinity maturation to acquire high avidity and more potent capacity to neutralize pathogens, activate the complement pathway, and kill infected cells through antibody-dependent cellular cytotoxicity (ADCC). IgG antibodies have a relatively long half-life in serum and are associated with B cell memory. IgG antibodies to SARS-CoV-2 do not develop until around 14 days post-infection [ 100 ]. A positive test for IgG is a good indication of having been infected or vaccinated. Interestingly, among those infected by SARS-CoV-2, detectable IgG antibodies are mainly IgG1 & IgG3 [ 101 ].

IgA antibodies are produced right following IgM with serum levels higher than IgM and are the main antibody class in mucosal surfaces and secretions. It has been reported that the SARS-CoV-2-specific IgA can be detected prior to the appearance of IgM and dominates the early neutralizing responses [ 102 ]. IgA forms dimers upon secretion to increase avidity. IgA antibodies secreted into the respiratory tract play a key role in mucosal immunity to SARS-CoV-2 infection by facilitating aggregation and preventing the initial infection of host cells. It is important to note that detectable levels of neutralizing antibodies against SARS-CoV-2 start declining within three months following mild and asymptomatic infections. This might predict transient immunity and heightened risk of reinfection.

Intriguingly, several groups have reported a clear association between the extent of T cell immunity and humoral response in convalescent individuals [ 103 , 104 , 105 ]. Patients with severe COVID-19 were found harboring low mutation frequencies in their heavy-chain variable region genes in the early weeks after infection, notably in those antibodies against the spike protein [ 106 ], indicating suboptimal immunoglobulin maturation. Furthermore, a delay in the emergence of antibodies, including the anti-SARS-CoV-2 neutralizing antibodies, has also been noted in severe forms compared with milder forms of COVID-19 [ 107 , 108 ]. These are in line with the fact that CD4 + T cells are essential for sustaining germinal center (GC) formation and B cell differentiation leading to isotype switch and immunoglobulin maturation, two features of T cell-dependent humoral response. Consistently, defective GC formation is associated with CD4 + T cell depletion in the lymph nodes of severe COVID-19 patients [ 109 ]. This defect and delay to develop antibodies against spike protein may contribute to viral dissemination and longer persistence of SARS-CoV-2 in patients [ 110 ]. Moreover, premature T cell depletion due to apoptosis was associated with a lower B-cell response in individuals infected with filovirus [ 111 ] or retrovirus [ 112 , 113 ]. Therefore, to what extent whereby the death of CD4 + T cells by apoptosis [ 114 ] may correlate with a delay in mounting an efficient humoral response and in developing sequelae merits further investigation.

Adaptive immunity: cellular immunity and resistance to SARS-CoV-2

Specific cellular immunity to SARS-CoV-2 is mediated by T cells. These cells are naïve and circulate in the bloodstream and peripheral lymphoid organs until encountering their specific antigen peptide presented by MHC. The SARS-CoV-2 virus itself or naked viral peptides could not activate T cells. High-affinity interaction between self MHC presented SARS-CoV-2 peptides and TCR induces proliferation and differentiation of T cells into cells capable of contributing to the removal of virus-infected cells or helping the production of antibodies. Class I MHC presented endogenous antigen peptides that activate CD8 + T cells, while class II MHC presented exogenous antigen peptides that activate CD4 + T cells. SARS-CoV-2 specific T cells are critical in the immunity to infection and susceptibility to severe disease has been reported to correlate with HLA alleles [ 115 ]. It is known that inflammatory monocytes and macrophages as well as DC express ACE2 which permits the entry of SARS-CoV-2 into these professional antigen-presenting cells to activate T cells, especially CD8 + T cells. Although the ACE2 expression on macrophages and DC is only at intermediate levels, the co-expression of CD209 (DC-SIGN) could dramatically facilitate SARS-CoV-2 entry into DC [ 116 ]. It should be pointed out that in most cases, SARS-CoV-2 infections do not elicit a dramatic inflammatory response in macrophages and DC. IL-6 is almost undetectable and other cytokines such as IL-1 are very low [ 117 ]. This may limit their migration to local lymphoid tissue and maturation to cells with the expression of co-stimulation molecules that are highly effective at presenting antigen to recirculating T cells, indicating a robust T cell response to SARS-CoV-2 may be difficult to induce and thus limit the development of immunity. It is important to note that B cells can also serve as SARS-CoV-2 antigen-presenting cells, especially those with surface immunoglobulin specific to SARS-CoV-2 antigens.

Patients with COVID-19 at the severe stage were manifested with decreased peripheral lymphocytes, termed lymphopenia or lymphocytopenia, which was believed to promote the disease progression [ 118 ]. Since lymphocytes barely express ACE2, it is unlikely to be a direct target of the SARS-CoV-2 virus [ 119 ]. Two major indirect mechanisms were proposed to account for lymphocyte loss. One is the enhanced cell-autonomous death, primarily by apoptosis. T cells isolated from patients with severe COVID-19 exhibited an increased propensity to die via apoptosis, as evidenced by a higher level of caspase activation and phosphatidylserine exposure, and a high rate of spontaneous apoptosis [ 114 ]. This was strongly associated with increased soluble Fas ligand in sera, and with increased expression of Fas/CD95 on T cells, particularly on CD4 + T cells [ 114 , 120 ]. While both extrinsic and intrinsic apoptosis, but not necroptosis, were found to be involved, treatment with Q-VD, a pan-caspase inhibitor, protected the isolated T cells from cell death and enhanced the expression of Th1 transcripts [ 114 ]. Consistently, TNF-α and IFN-γ were found prominently upregulated in the sera of patients with severe COVID-19, which was related to a phenomenon called cytokine storm or also viral sepsis [ 31 ]. This phenomenon is at least in part induced by an inflammatory cell death PANoptosis, abbreviated for the mixed cell death of pyroptosis, apoptosis, and necroptosis. Importantly, the TNF-α/IFN-γ-induced lethality in animals could be rescued, along with the increased level of T cells, in Ripk3 ‒/‒ Casp8 ‒/‒ mice, in which PANoptosis was suppressed [ 121 ].

Another mechanism responsible for lymphocyte loss is non-autonomously mediated by syncytia, which could be efficiently induced by SARS-CoV-2 via its fusogenic spike protein dictated by an embedded bi-arginine motif [ 122 ]. The multinucleated syncytia were found to be able to internalize infiltrated live lymphocytes, preferentially the CD8 + T cells, to form cell-in-cell structures, a unique phenomenon that is prevalent in tumor tissues [ 123 ] and plays important roles in clonal selection and immune homeostasis and the like [ 124 , 125 , 126 ]. By defaults, as taking place in cancer cells, the formation of the cell-in-cell structure primarily resulted in the death of the internalized lymphocytes within syncytia, leading to a rapid elimination, which could be rescued by either blocking syncytia formation or cell-in-cell-mediated death, thus providing a novel target for COVID-19 therapy [ 127 , 128 , 129 , 130 ]. Interestingly, the two lymphopenia mechanisms seem to exhibit a preference for the targeted lymphocytes, with the autonomous one for CD4 + T cells while the non-autonomous one for CD8 + T cells [ 114 , 122 ], whether the preference also applies to other types of lymphocytes and its biological properties and potential implications warrant further investigation. In addition to directly regulating the cellularity of lymphocytes, syncytia were recently shown to be able to activate the cGAS-STING signaling via inducing the naked cytoplasmic micronuclei [ 95 , 96 ], and to initiate inflammatory cell death [ 131 ], both of which, though may help mount an anti-infection immunity, would eventually promote inflammation and tissue damages leading to severer clinical conditions. Coincidently, the less pathogenic Omicron variant of SARS-CoV-2 displayed a compromised ability to induce syncytia formation in cells expressing human ACE2 [ 132 , 133 , 134 ]. Together, syncytia and various types of cell death may serve as an important hub for pathogenesis induced by SARS-CoV-2 infection.

Though it is generally recognized that T cell immunity plays a central role in the control of SARS-CoV-2, its importance is still underestimated and mechanistically unclear. A proper T cell response is important to limit infection. Unlike antibodies, which are less sustained and only those specific to RBD can neutralize, T cells react to at least 30 epitopes of viral proteins and exhibit sustained memory. That CD4 + T cells are more prone to undergo apoptosis may also contribute to the development of “helpless” CD8 + T cells, which are exhausted and shorter-lived cells [ 135 , 136 ], leading to defective T cell toxicity [ 137 ] and death of CD8 + T cells [ 114 ] in patients with severe COVID-19. In addition, the aforementioned highly activated CD16 + T cells also contribute to the pathophysiology of COVID-19 [ 49 ]. Thus, preventing lymphopenia, the death of T cells, and the inappropriate functionality of CD16 + T cells could be of interest to limit pathogenicity and probably long-term sequela. Consistently, the use of caspase inhibitor in the early phase of infection has provided protection for monkeys developing acquired immunodeficiency syndrome (AIDS) [ 138 ]. Therefore, similar strategies might be of interest for SARS-CoV-2 infection. Meanwhile, although COVID-19 in children is rarely severe, a subset of patients developed multisystem inflammatory syndrome in children with robust type II interferon and NF-kB responses, manifested by a transient expansion of TRBV11-2 T cell clonotypes and signs of inflammatory T cell activation [ 139 ]. An association with HLA A*02, B*35 and C*04 alleles suggests a genetic predisposition, yet to be validated in larger cohorts [ 139 ].

Whilst physical and mental stresses, either acute or chronic, have a dramatic impact on the immune system, both innate and adaptive immune components could be affected. Humans and animals subjected to stress conditions exhibited significant reduction in lymphocytes [ 140 ], increase in IL-6 production [ 141 ], decrease in IFN-γ [ 142 ], augmentation in regulatory T cells [ 142 ], and alteration in gut microbiota [ 143 ]. The induction of Fas expression on lymphocytes by chronic stress [ 144 ] could account, at least in part, for the lymphopenia development in COVID-19 patients mentioned above. It is imperative to emphasize that the prevalence of stress associated with anxiety, depression, fear, and inadequate social support during the COVID-19 pandemic should not be ignored. There is a strong need to understand the stress impact on COVID-19 experiences and stress management should be included in the care of patients, especially those suffering from mental and psychological disorders.

Therapeutic antibody against SARS-CoV-2

Monoclonals, whether of animal or human origin, have been used for the development of most non polymerase chain reaction (PCR)-based diagnostic tests. They usually target the nucleocapsid, which is the most abundant protein of the virus. During the pandemic, they have been used in hundreds of millions of rapid tests. Herein, we will focus our attention on the use of human monoclonal antibodies (hmAbs). Before the SARS-CoV-2 pandemic, hmAbs had been widely used to treat cancer, inflammatory and autoimmune diseases [ 145 ]. With the exception of an antibody against the respiratory syncytial virus approved for clinical use in 1998 [ 146 ], hmAbs had not been used for infectious diseases because they require large quantities to be delivered intravenously and were too expensive compared to infectious disease standard of care. The game started to change with a pioneering work done by Antonio Lanzavecchia during the 2002–2003 outbreak of SARS-CoV-1 [ 147 ]. For the first time, his lab was able to clone from a convalescent patient a B cell producing antibody neutralizing the virus. Since then, many other technologies became available to isolate hmAbs starting from the B cells of convalescent or vaccinated donors. Many antibodies were developed and tested in the clinic for HIV, and the improved technology allowed to isolate antibodies that were more than 1000-fold more potent of the ones initially isolated against this pathogen [ 148 ]. In this environment, the Wellcome Trust published in 2019 a report stating that the time to develop hmAbs for infectious diseases was mature (Wellcome Trust. “Expanding Access to Monoclonal Antibody-Based Products.” (2020)).

As soon as the SARS-CoV-2 pandemic started, multiple academic and industrial laboratories isolated B cells from convalescent people and generated numerous publications in prestigious journals showing the identification of hmAbs able to neutralize the virus in vitro, as well as protecting and treating mice, hamsters, and non-human primates in vivo from viral challenge [ 149 ]. The neutralizing antibodies are usually divided into four classes which bind different regions of the spike, Fig.  5 . In addition to the pre-clinical evidence, several clinical studies showed that, when used early after infection, hmAbs had very high efficacy in preventing severe disease [ 150 ]. Given their efficacy, and since these were the first therapeutic molecules developed during the pandemic, numerous hmAbs received emergency use in the US and Europe: REGN COV2 (Casirivimab and Imdevimab), Bamlanivimab (LY-CoV555), Sotrovimab (VIR 7831 or S309), Evusheld (tixagevimab and cilgavimab) and Bebtelovimab (LY-CoV1404) [ 150 ]. For more than one year, hmAbs remained the only real therapeutic tool we had against SARS-CoV-2. Unfortunately, hmAbs did not work in a therapeutic setting during advanced severe disease in hospitalized patients and many of them fell short with the emergence of SARS-CoV-2 variants carrying different mutations on the spike protein, the major target for neutralizing hmAbs. In fact, with the emergence of the SARS-CoV-2 Omicron variant, 85% of hmAbs approved for clinical use lost their potency against this virus [ 151 ]. Today we still have three approved hmAbs that work reasonably well against Omicron and new potent monoclonals against this variant are described in the literature [ 151 ]. In conclusion, the COVID-19 pandemic has suggested prevention and therapeutic potential of hmAbs to infectious diseases and that can be developed faster than any other medicine. In addition, it is now possible to develop extremely potent hmAbs that can be administered intramuscularly rather than intravenously, facilitating their administration outside the hospital. Therefore, hmAbs can be considered at the forefront of medical interventions in the field of infectious diseases as their characteristics make them essential tools to tackle emerging pathogens and pandemics.

The potency and breadth of neutralization across SARS-CoV-2 variants are denoted for each antibody class [ 171 , 172 , 173 ].

The SARS-CoV-2 vaccination

Exposure to attenuated pathogens or parts of the pathogens to induce specific immunity against a pathogen started with smallpox variolation in China more than 1000 years ago [ 152 ]. Edward Jenner employed cowpox to protect humans from smallpox 800 years later. Since in Latin the word Vacca is for cow, the term vaccination is adapted later by Jenner’s friend Richard Dunning in 1800. In the last 200 years, various approaches have been developed to shelter human beings from different infections through vaccination. One of the most impressive results of modern medicine is the development of highly effective vaccines against SARS-CoV-2 in less than one year from the beginning of the pandemic, Fig.  6 . Since the appearance of SARS-CoV-2, scientists have tried different ways to develop vaccines and the most significant ones include modified mRNA encoding S-protein (Moderna and BioNTech), the replication-defective viral vector containing the S-protein sequence (Ad5-nCov-CanSino, ChAdOx1 based AZD1222-A-AstraZeneca, GRAd-COV2-Reithera), inactivated pathogenic SARS-CoV-2 (SinoVac, SinoPharm), and recombinant viral subunit proteins (entire S-protein or RBD), Table  1 . Among the 10 billion doses delivered, so far the mRNA vaccines from BioNTech and Moderna as well as the viral vector-based vaccine from AstraZeneca and the inactivated vaccines from Sinovac and Sinopharm occupy more than 95% of the market.

Inactivated SARS-CoV-2 vaccine reserves all viral proteins for immune recognition. Once immunized, these antigens could elicit a T helper pool broadly targeting SARS-CoV-2 proteins. mRNA vaccine, on the other hand, elicits strong humoral and cellular immune responses against the SARS-CoV-2 variants in individuals who previously received the inactivated vaccine. We hypothesized that the T helper pool primed by inactivated vaccine could be activated upon mRNA vaccination, which facilitates the building of stronger immune response and memory.

Due to the emergency of the COVID-19 pandemic, scientists did have the minimum sufficient time to evaluate the effectiveness of vaccines developed, and there is large scope for improvement. For example, the interval between doses (21 days for Pfizer; 28 days for Moderna) seems too short, and understanding of the short-lived antibody response (6 months) is still elusive. The cross-reactivity with SARS and MERS might suggest the possibility of a universal pan-coronavirus vaccine. More, as in other vaccinations, there is the possibility that specific commensal microbiota, helminths, nutrients (bile acids, butyrates) or antibiotics, not to mention an immune-suppressive status, might impair the immune response. So far, there are two most popular methods, antibody levels and protection from infection in the real world, to evaluate the effectiveness of a vaccine. Clearly, the antibody is a good predictor and there are epidemiological data supporting a good correlation between the antibody level and disease susceptibility [ 153 ], especially considering the complexity of antibody classes and their kinetics. Since the vaccines can only provide a reduction in severity, there is no good model and specifics to quantitatively analyze and accurately determine the protectability.

We have previously hypothesized that “there are many types or subtypes of coronavirus” -or variants. Thus, if vaccines directly targeting SARS-CoV-2 prove to be difficult to develop, the Edward Jenner approach should be considered [ 154 ]. It has been noted that a subset of T cells primed against seasonal coronaviruses cross-react with SARS-CoV-2, and this is believed that it may contribute to clinical protection, particularly in early life. The coronaviruses belong to a family of enveloped single-stranded positive-sense RNA viruses. Available information on cellular immunity to other human coronaviruses (HCoVs), especially those causing the common cold, could be valuable for elucidating immunity to SARS-CoV-2. It is estimated that >90% of adults have experienced prior exposure to common cold viruses. Whether the cellular immunity to other coronaviruses such as SARS-CoV-1 last is still a question, though it has been shown that T cell responses can be elicited after 17 years [ 155 ]. Sustained T cell responses have been seen in some patients infected with MERS, though remain to be verified with longitudinal studies in more patients. Considering the wide distribution of horseshoe bats in Southeast Asia and the low SARS-CoV-2 infection rate in the area (3.1% in Southeast Asia, 14.9% in the Americas, and 22.5% In Europe according to the data on WHO COVID-19 Dashboard as of February 2022), it is suggestive that some bat coronavirus(es) may provide natural immunity to native residents. As Edward Jenner did with the cowpox virus to protect humans from smallpox, we may try to identify a bat coronavirus to protect humans from SARS-CoV-2.

A successful vaccine relies on various factors such as the identification of the effective epitopes or viral components, the delivery vectors, proper adjuvant, administration routes and the physical and medical conditions of the recipients [ 156 ]. Even if we have effective vaccines, the vaccination rate in a given time, social acceptability/resistance, and inadequate social distance may allow the virus to present in a population for sufficiently long to mutate [ 157 ]. As it stands at the moment, none of the available vaccine formulations seem to be capable of completely preventing virus infection, at least when it comes to highly infective variants such as the Omicron variant. What needs to be considered under these circumstances with often only partial immune protective conditions is that the virus is subjected to an unfavorable situation that may force the virus to mutate.

What will follow Omicron

Among all the variants of SARS-CoV-2, Omicron brings the most worries, confusion, and expectations. The fast transmission rate of the Omicron variant has raised serious concerns among epidemiologists, politicians, and disease control experts since it was first reported from South Africa on November 24, 2021 [ 158 ]. Many factors contribute to the fast spread. It is possible that the virus begins to spread shortly after the initial infection and long before the appearance of symptoms. Omicron is approximately 10 times more contagious than wild-type SARS-CoV-2 or 2.8 times as infectious as Delta. The newly emerged new Omicron BA.2 is even more contagious [ 159 ]. Mutation analysis of Omicron and its BA.2 variants indicates that their spike proteins carry large amounts of mutations far more than the previous VoC, Fig.  1 . Of the mutations, D614G is a well-known mutation that confers enhanced infectivity by multiple mechanisms including a bi-modular impact on the stability of spike trimer [ 160 , 161 ]; the mutations in K417 and E484 of the RBD region were believed to alter spike affinity to ACE2 [ 162 ]; the N501Y mutation had been shown to change virus tropism by endowing cross-species transmission to mice [ 163 ], therefore creating a potential intermediate host that helps virus spreading [ 164 ]. Indeed, latest studies identified Omicron infection in rats and mice [ 165 , 166 , 167 ], supporting the zoonotic transmission of the new SARS-CoV-2 variant of concerns. It is expected that the mutations in the Omicron RBD together altered the affinity to ACE2, however, protein structural analysis did not find a higher affinity [ 168 ]. The contributing factors to the highly contagious nature remain a mystery. Nevertheless, the high ability to spread and the seemingly less pathogenicity have ignited the hope of herd immunity and the ending of the pandemic. The question is whether Omicron is indeed less pathogenic now but can acquire increased pathogenicity through further mutations. There is no guarantee that the next variant will be milder. The most worrisome is the appearance of Deltacron, which has the backbone of the Delta variant and the spike of Omicron. Information on the transmission speed and pathogenicity of Deltacron is urgently needed.

There is a lot of debate regarding the effectiveness of the existing vaccines against Omicron. Almost all vaccine-induced immunity could be invaded by the Omicron variant. Due to their lower ability to induce antibodies, the inactivated vaccines are believed to be not as effective in providing protection against infection. Scientists are waiting for the recent information on the disease severity of patients infected with Omicron from China mainland, where nearly 90% have received inactivated vaccines, and that from Hong Kong, where the majority of people are immunized with the RNA vaccines. It should be noted that a multinational study showed that recipients immunized first with inactivated vaccine followed by an RNA vaccine showed the highest RBD specific antibody and Omicron specific T cells as compared to two immunizations with a single vaccine type. May inactivated vaccine induces more T helper cells due to being presented by MHC class II, Fig.  6 ? It has been reported that heterologous immunization with inactivated vaccine followed by an mRNA booster elicits strong humoral and cellular immune responses against the SARS-CoV-2 Omicron variant [ 169 ].

Finally, how will the COVID-19 pandemic end? Will Omicron be the last variant? If not, what properties will the next variant have? The biggest question is whether COVID-19 will become endemic. We just hope that, with the immunity built up by vaccination and infection in the population, the endemic is not as deadly. Clearly, we have to learn the new routines of SARS-CoV-2.

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Acknowledgements

The authors thank Eleonora Candi and Richard Knight for their helpful and constructive criticisms.

This work has been supported by the Associazione Italiana per la Ricerca contro il Cancro (AIRC) to GM (IG#20473; 2018–2022), to IA (AIRC Start-Up ID 23219; 2020–2024). Work has been also supported by Regione Lazio through LazioInnova Progetto Gruppo di Ricerca n 85-2017-14986; n 33 & 55-2021-T0002E0001, by grants CRC1454 432325352 and CRC1403 414786233 to EL from the Deutsche Forschungsgemeinschaft (DFG) and the grant COVIMMUNE to EL by the Bundesministerium für Bildung und Forschung (BMBF), and by grant CRC1454 432325352 to JLS from the DFG and the grant COVIM to JLS by the BMBF. AM is supported by a grant from the Italian Ministry of Health, to JE from the Fondation Recherche Médicale and the Agence Nationale de la Recherche (COVID-I²A) and from Canada Research Chair program. Work has been supported by grants from the National Key R&D Program of China (2018YFA0107500, 2021YFA1100600 and 2022YFC3600100), the Scientific Innovation Project of the Chinese Academy of Sciences (XDA16020403), the National Natural Science Foundation of China (81861138015, 81530043, 31961133024, 32000626, 81930085 32150710523, and 81571612), Fellowship of China Postdoctoral Science Foundation (2020M671261), Ministry of Health Italy-China cooperation grant & AIRC IG#20473 to GM. Jiangsu Province International Science and Technology Cooperation Program (BZ2019017), National Center for International Research-Cambridge-Su Genomic Research Center (2017B01012) and the State Key Laboratory of Radiation Medicine and Protection, Soochow University (GZN1201903).

Author information

These authors contributed equally: Qing Li, Ying Wang, Qiang Sun.

Authors and Affiliations

The Third Affiliated Hospital of Soochow University/The First People’s Hospital of Changzhou, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine of Soochow University, Medical College, Suzhou, China

Qing Li, Jingting Jiang, Changshun Shao, Peishan Li, Xiaozhou He, Fei Hua & Yufang Shi

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

Ying Wang, Liangyu Lin & Yufang Shi

Beijing Institute of Biotechnology, Research Unit of Cell Death Mechanism, Chinese Academy of Medical Sciences, 2021RU008, 20 Dongda Street, 100071, Beijing, China

Qiang Sun, Zubiao Niu, Chaobing Ma & Yichao Zhu

Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany

Jasmin Knopf & Martin Herrmann

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen‐Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany

Ministry of Health, Rome, Italy

Giuseppe Ippolito

Department of Biology, TOR, University of Rome Tor Vergata, 00133, Rome, Italy

Mauro Piacentini & Sonia Melino

INSERM-U1124, Université Paris, Paris, France

Jerome Estaquier

CHU de Québec - Université Laval Research Center, Québec City, QC, Canada

Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127, Bonn, Germany

Felix Daniel Weiss & Eicke Latz

Research and Development Center, GlaxoSmithKline (GSK), Siena, Italy

Emanuele Andreano & Rino Rappuoli

Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany

Eicke Latz, Joachim L. Schultze & Gerry Melino

Genomics & Immunoregulation, LIMES-Institute, University of Bonn, Bonn, Germany

Joachim L. Schultze

Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, Pieve Emanuele, 20072, Milan, Italy

Alberto Mantovani

IRCCS Humanitas Clinical Research Hospital, via Manzoni 56, Rozzano, 20089, Milan, Italy

William Harvey Research Institute, Queen Mary University, London, UK

Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada

Tak Wah Mak

Department of Pathology, University of Hong Kong, Hong Kong, Pok Fu Lam, 999077, Hong Kong

Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy

Gerry Melino & Yufang Shi

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GM and YS conceived the project; all authors wrote the manuscript; QS and ZN prepared Fig.  1 ; JK and MH Fig.  2 ; QS and CM Fig.  3 ; QL and YW Figs.  4 and 6 ; JS Fig.  5 ; YW and YS Table  1 .

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Li, Q., Wang, Y., Sun, Q. et al. Immune response in COVID-19: what is next?. Cell Death Differ 29 , 1107–1122 (2022). https://doi.org/10.1038/s41418-022-01015-x

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Received : 11 April 2022

Revised : 16 April 2022

Accepted : 26 April 2022

Published : 17 May 2022

Issue Date : June 2022

DOI : https://doi.org/10.1038/s41418-022-01015-x

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SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development

The pandemic of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing great threats to the world in many aspects. Effective therapeutic and preventive approaches including drugs and vaccines are still unavailable although they are in development. Comprehensive understandings on the life logic of SARS-CoV-2 and the interaction of the virus with hosts are fundamentally important in the fight against SARS-CoV-2. In this review, we briefly summarized the current advances in SARS-CoV-2 research, including the epidemic situation and epidemiological characteristics of the caused disease COVID-19. We further discussed the biology of SARS-CoV-2, including the origin, evolution, and receptor recognition mechanism of SARS-CoV-2. And particularly, we introduced the protein structures of SARS-CoV-2 and structure-based therapeutics development including antibodies, antiviral compounds, and vaccines, and indicated the limitations and perspectives of SARS-CoV-2 research. We wish the information provided by this review may be helpful to the global battle against SARS-CoV-2 infection.

General Information of SARS-CoV-2

Current situation of sars-cov-2 epidemic.

In December 2019, the World Health Organization (WHO) was informed about an outbreak of pneumonia in Wuhan, Hubei Province, China, and the etiology was not identified. On January 30, 2020, WHO declared that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic is a public health emergency of international concern (PHEIC). On February 11, 2020, the WHO officially named the current outbreak of coronavirus disease as Coronavirus Disease-2019 (COVID-19) ( Sun P. et al., 2020 ) and the International Committee on Taxonomy of Viruses (ICTV) named the virus as SARS-CoV-2 ( Hu B. et al., 2020 ). Data as received by WHO from national authorities by October 11, 2020, there were more than 37 million confirmed cases with COVID-19 and 1 million deaths. Globally, the United States, India, and Brazil are the three countries with the largest cumulative number of confirmed cases in the world ( https://www.who.int/docs/default-source/coronaviruse/situation-reports/20201012-weekly-epi-update-9.pdf ). The total cumulative number of confirmed cases have far exceeded the number during SARS period ( Wang and Jin, 2020 ). After the emergence of SARS-CoV and MERS-CoV, SARS-CoV-2 is the third zoonotic human coronavirus of the century ( Gralinski and Menachery, 2020 ).

The Origin and Evolution of SARS-CoV-2

Bioinformatic analyses showed that SARS-CoV-2 had characteristics typical of coronavirus family. It belongs to the betacoronavirus 2B lineage ( Lai et al., 2020 ). Early in the pneumonia epidemic in Wuhan, scientists obtained the complete genome sequences from five patients infected with SARS-CoV-2. These genome sequences share 79.5% sequence identity to SARS-CoV. Obviously, SARS-CoV-2 is divergent from SARS-CoV. It is considered to be a new betacoronavirus that infects human ( Zhou P. et al., 2020 ). Scientists aligned the full-length genome sequence of SARS-CoV-2 and other available genomes of betacoronaviruses. Results indicate the closest relationship of SARS-CoV-2 with the bat SARS-like coronavirus strain BatCov RaTG13, with an identity of 96%. These studies suggest that SARS-CoV-2 could be of bat origin, and SARS-CoV-2 might be naturally evolved from bat coronavirus RaTG13 ( Zhang C. et al., 2020 ; Zhou P. et al., 2020 ).

One study analyzed the genomes of SARS-CoV-2 and similar isolates from the GISATD and NCBI ( Xiong C. et al., 2020 ). Results indicate that an isolate numbered EPI_ISL_403928 shows different genetic distances of the whole length genome and different phylogenetic trees, the coding sequences of spike protein (S), nucleoprotein (N), and polyprotein (P) from other SARS-CoV-2, with 4, 2, and 22 variations in S, N, and P at the level of amino acid residues respectively. The results show that at least two SARS-CoV-2 strains are involved in the outbreak ( Xiong C. et al., 2020 ).

After aligning the coding sequences (CDSs) based on the protein alignments, open reading frame 8 (ORF8) and open reading frame 10 (ORF10) of SARS-CoV-2 are different from other viruses. However, most ORFs annotated from SARS-CoV-2 are conserved. The overall genomic nucleotides identity between SARS-CoV-2 and SARS-like coronavirus strain BatCov RaTG13 is 96%. Compared with other viruses, the divergence of SARS-CoV-2 at neutral site is 17%, much larger than previously assessed. The spike gene exhibits larger dS (synonymous substitutions per synonymous site) values than other genes, which could be caused either by natural selection that accelerates synonymous substitutions or by a high mutation rate. Researchers obtained 103 SARS-CoV-2 genomes to recognize the genetic variants ( Tang X. et al., 2020 ). Among the 103 strains, a total of 149 mutations are identified and population genetic analyses indicate that these strains are mainly divided into two types. Results suggest that 101 of the 103 SARS-CoV-2 strains show significant linkage between the two single nucleotide polypeptides (SNPs). The major types of SARS-CoV-2 (L type and S type) are distinguished by two SNPs which locate at the sites of 8,782 and 28,144. L type accounts for 70% of the 103 strains and S type accounts for 30%, suggesting L type is more prevalent than the S type. However, S type is the ancestral version of SARS-CoV-2 ( Tang X. et al., 2020 ).

To date, 13 mutations in the spike protein have been identified. The mutation D614G should be paid special attention. In early February, the mutation Spike D614G began spreading in Europe. When introduced to new regions, it rapidly replaced the original strain to become the dominant strain ( Korber B. et al., 2020 ). The D614G mutation in the spike protein would increase infectivity. S G614 is more stable than S D641 and less S1 shedding are observed, so the SARS-CoV-2 with S G614 could transmit more efficiently ( Zhang et al., 2020b ). One study shows that in multiple cell lines, the SARS-CoV-2 carrying the D614G mutation is eight times more effective at transducing cells than wild-type spike protein, providing evidence that the D614G mutation in SARS-CoV-2 spike protein could increase the transduction of multiple human cell types ( Daniloski Z. et al., 2020) . The D614G mutation could also decrease neutralization sensitivity to the sera of convalescent COVID-19 patients ( Hu J. et al., 2020 ).

The Epidemiological Characteristics of COVID-19

Bats appear to be the natural reservoir of SARS-CoV-2 ( Zhang C. et al., 2020 ; Zhou P. et al., 2020 ). In one study, betacoronavirus isolated from pangolins has a sequence similarity of up to 99% with the currently infected human strain ( Liu et al., 2020 ). Another study indicates that SARS-CoV-2 and the coronavirus from a pangolin in Malaysia has high genetic similarity. The gene similarity between these two viruses in terms of E, M, N, and S genes is 100, 98.6, 97.8, and 90.7%, respectively, suggesting the potential for pangolins to be the intermediate host ( Xiao et al., 2020 ). Among the animals in close contact with humans, dogs, chickens, ducks, and pigs are not permissive to infection. SARS-CoV-2 replicates efficiently in cats and ferrets ( Shi J. et al., 2020 ). SARS-CoV-2 can also transmit in golden hamster ( Sia et al., 2020 ).

SARS-CoV-2 is transmitted via fomites and droplets during close unprotected contact between the infected and uninfected. Symptomatic and asymptomatic patients are the main source of infection. The virus can also spread through indirect contact transmission. Virus-containing droplets contaminate hands, people then contact the mucous membranes of the mouth, nose, and eyes, causing infection. The transmission of SARS-CoV-2 is not limited to the respiratory tract ( Du et al., 2020 ). Some studies have demonstrated the aerosol transmission of SARS-CoV-2. During the COVID-19 outbreak, one study investigated the aerodynamic nature of SARS-CoV-2 by measuring viral RNA in aerosols in two Wuhan hospitals, indicating that SARS-CoV-2 has the potential to spread through aerosols. There may be a possibility of airborne transmission in health care facilities due to aerosols generated by medical procedures. Of note, in the spread of COVID-19, airborne transmission is the dominant route. ( Chan et al., 2020 ; Meselson, 2020 ; Morawska and Cao, 2020 ; Sommerstein et al., 2020 ; Tang S. et al., 2020 ; van Doremalen et al., 2020 ; Zhang R. et al., 2020 ). In some pediatric SARS-CoV-2 infection cases, although children’s nasopharyngeal swabs are negative, rectal swabs are consistently positive, indicating the possibility of fecal-oral transmission ( Xu et al., 2020 ). Recent studies demonstrate that SARS-CoV-2 could replicate effectively in human intestinal organoids and intestinal epithelium. As a result, SARS-CoV-2 has the potential to spread through intestinal tract. SARS-CoV-2 can also infect the intestinal cells of bats ( Lamers et al., 2020 ; Zhou J. et al., 2020 ). A COVID-19 patient’s urine also contains infectious SARS-CoV-2 ( Sun J. et al., 2020 ). After studying COVID-19 infection in nine pregnant women, the result suggests that there is no evidence that pregnant women who were infected SARS-CoV-2 in late pregnancy can transmit the virus to infant through intrauterine vertical transmission ( Chen N. et al., 2020 ). However, recently, some studies demonstrated the possibility of vertical transmission of SARS-CoV-2 ( Chen H. et al., 2020 ; Deniz and Tezer, 2020 ; Egloff et al., 2020 ; Hu X. et al., 2020 ; Mahyuddin et al., 2020 ; Oliveira et al., 2020 ; Parazzini et al., 2020 ; Peyronnet et al., 2020 ; Vivanti et al., 2020 ; Yang and Liu, 2020 ). In one case, the newborn whose mother was diagnosed with SARS-CoV-2 in the last trimester was infected with SARS-CoV-2, with neurological compromise. In another case, the cytokine levels and anti-SARS-CoV-2 IgM antibodies of the neonate is higher than normal, with no physical contact, suggesting the possibility of transplacental transmission ( Dong et al., 2020 ). The risk of perinatal transmission of SARS-CoV-2 is relatively low. Compared with SARS-CoV-2, pregnant women infected with SARS and MERS showed more severe symptoms, such as miscarriage and abortion ( Fan et al., 2020 ; Parazzini et al., 2020 ). According to current reports, the perinatal transmission can occur but the rate is low and the information about exposition during the first or second trimester of pregnancy remains unknown ( Egloff et al., 2020 ; Parazzini et al., 2020 ). The major spread route of SARS-CoV-2 is person-to-person, it could happen in family, hospital, community, and other gathering of people. Most cases of the person-to-person transmission of the early stage in China happened in family clusters ( Chan et al., 2020 ; Ghinai et al., 2020a ; Ghinai et al., 2020b ). This kind of spreading has the possibility to occur during the incubation period ( Yu P. et al., 2020 ). It is worth noting that SARS-CoV-2 has high transmissibility during asymptomatic period or mild disease ( Hu B. et al., 2020 ; Li et al., 2020 ). SARS-CoV-2 can also transmit from human to animal. Some animals, such as tiger, dog, and cat, are found to be infected with the virus through close contact with the infected people ( Singla et al., 2020 ). A 17-years-old dog in Hong Kong was affected and it was the first case of human-to-animal transmission ( https://www.afcd.gov.hk/english/publications/publi cationspress/pr2342.html ). One study shows that the viral genetic sequences of SARS-CoV-2 detected in two dogs are the same with the SARS-CoV-2 in the corresponding human cases, suggesting the human-to-animal transmission. However, it remains unknown whether infected dogs can transmit the virus back to humans ( Sit et al., 2020 ). SARS-CoV-2 is believed to transmit from the animal kingdom to human. According to the sequence analysis, bats are natural hosts for SARS-CoV-2 ( Cui et al., 2019 ; Salata et al., 2019 ). SARS-CoV-2 and the coronavirus from a pangolin in Malaysia have high genetic similarity ( Xiao et al., 2020 ), and the CoVs isolated from pangolins have the highest closeness to SARS-CoV-2 ( Zhang T. et al., 2020 ), suggesting the potential for pangolins to be the intermediate host. The intermediate hosts could transmit the virus to susceptible people, leading to the newly appear diseases in humans ( Ye et al., 2020 ; Zhang T. et al., 2020 ). SARS-CoV-2 can also transmit between animals. SARS-CoV-2 infected cats could transmit the virus to naïve cats with close contact ( Halfmann et al., 2020 ). SARS-CoV-2 could also transmit in naïve ferrets, through direct or indirect contact ( Kim et al., 2020 ).

According to current observed epidemiologic characteristics, everyone is considered susceptible and the median age is about 50 years ( Chen N. et al., 2020 ; Guan et al., 2020 ; Huang et al., 2020 ; Wang D. et al., 2020 ; Wu and McGoogan, 2020 ).

The clinical manifestations differ with age. One study indicates that the cases over 60 years old have higher levels of blood urea nitrogen, inflammatory indicators, and more lobes bilateral lesions. The patients older than 60 years old have a greater chance of respiratory failure and longer disease courses. However, in those under 60, the severity is milder ( Liu et al., 2020 ). One study reports a total of 72,314 confirmed cases in China, the majority of the patients (87%) are between the ages of 30 and 79. In the group no older than nine, no deaths occurred. However, in the group aged 70−79 years, the case-fatality rate (CFR) is 8.0%, in the group aged 80 years and older, the CFR is 14.8%. As to the patients with different comorbid conditions, such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and cancer, the CFR is 10.5, 7.3, 6.3, 6.0, and 5.6%, respectively. These results suggest that comorbid conditions are high risk factors for COVID-19 patients and higher fatality rates are observed than those without underlying diseases ( Wu and McGoogan, 2020 ). Among the 1,099 cases confirmed with COVID-19, patients with severe disease were 7 years older than those with non-severe disease ( Guan et al., 2020 ). Of the 1,391 infected children, the median age is 6.7 years and most children show milder symptoms (non-pneumonia or mild pneumonia) than adults ( Lu X. et al., 2020 ). The patients who aged ≥65 years old have a higher risk of mortality from COVID-19, especially the patients with acute respiratory distress syndrome (ARDS) and comorbidities ( Du et al., 2020 ; Wu C. et al., 2020 ; Yang X. et al., 2020 ; Zhou F. et al., 2020 ).

Clinical Characteristics of COVID-19

The most common manifestations of COVID-19 are fever and dry cough. The majority of the patients showed bilateral pneumonia. Old males with comorbidities are more likely to be affected by SARS-CoV-2 ( Chen N. et al., 2020 ). The blood counts of patients showed leucopenia and lymphopenia. The content of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα in the plasma of ICU patients is higher than non-ICU patients ( Huang et al., 2020 ).

COVID-19 is divided into three levels according to the severity of the disease: mild, severe, and critical. The majority of patients only have mild symptoms and recover ( Hu B. et al., 2020 ). Asymptomatic infection cases were also reported, but most of the asymptomatic patients went on to develop disease since the data of identification ( Huang et al., 2020 ). Table 1 shows the clinical manifestations of COVID-19 ( Chen T. et al., 2020 ; Hu B. et al., 2020 ; Huang et al., 2020 ; Wang Y. et al., 2020 ; Wu and McGoogan, 2020 ) and three different levels of COVID-19 divided according to the severity ( Chen T. et al., 2020 ; Hu B. et al., 2020 ; Huang et al., 2020 ; Wang Y. et al., 2020 ; Wu and McGoogan, 2020 ). Besides respiratory illness, COVID-19 disease could lead to myocardial injury and arrhythmic complications ( Bansal, 2020 ; Kochi et al., 2020 ), neurological complications, such as myalgia, headache, dizziness, impaired consciousness, intracranial hemorrhage, hypogeusia, and hyposmia ( Berger, 2020 ; Paybast et al., 2020 ), and even stroke ( Hess et al., 2020 ; Trejo-Gabriel-Galán, 2020 ). Digestive symptoms and liver injury ( Lee et al., 2020 ), hypercoagulability and thrombotic complications ( Haimei, 2020 ) have also been reported. Critical patients could quickly progress to ARDS, hard-to-correct metabolic acidosis, septic shock, coagulation dysfunction, and multiple organ functional failure. Severe complications included ARDS, RNAaemia (detectable serum SARS-CoV-2 viral load), multiple organ failure, and acute cardiac injury. About 26.1% patients were admitted to the ICU because of complications caused by COVID-19 ( Huang et al., 2020 ). With proper diagnosis and treatments for COVID-19, most patients had a good prognosis ( Wang Y. et al., 2020 ). The elderly and the patients with underlying diseases have worse prognosis ( Deng and Peng, 2020 ).

Clinical manifestations and three different levels of COVID-19.

The Structure of SARS-CoV-2

Coronaviruses belongs to the subfamily Coronavirinae in the family of Coronaviridae and the subfamily contains four genera: Alphacoronavirus , Betacoronavirus , Gammacoronavirus , and Deltacoronavirus . The genome of CoVs (27–32 kb) is a single-stranded positive-sense RNA (+ssRNA) which is larger than any other RNA viruses. The nucleocapsid protein (N) formed the capsid outside the genome and the genome is further packed by an envelope which is associated with three structural proteins: membrane protein (M), spike protein (S), and envelope protein (E) ( Brian and Baric, 2005 ). As a member of coronavirus family, the genome size of SARS-CoV-2 which was sequenced recently is approximately 29.9 kb ( Lu R. et al., 2020 ). SARS-CoV-2 contains four structural proteins (S, E, M, and N) and sixteen non-structural proteins (nsp1−16). Nsp1 mediates RNA processing and replication. Nsp2 modulates the survival signaling pathway of host cell. Nsp3 is believed to separate the translated protein. Nsp4 contains transmembrane domain 2 (TM2) and modifies ER membranes. Nsp5 participates in the process of polyprotein during replication. Nsp6 is a presumptive transmembrane domain. The presence of nsp7 and nsp8 significantly increased the combination of nsp12 and template-primer RNA. Nsp9 functions as an ssRNA-binding protein. Nsp10 is critical for the cap methylation of viral mRNAs. Nsp12 contains the RNA-dependent RNA polymerase (RdRp), which is a critical composition of coronavirus replication/transcription. Nsp13 binds with ATP and the zinc-binding domain in nsp13 participates in the process of replication and transcription. Nsp14 is a proofreading exoribonuclease domain. Nsp15 has Mn(2+)-dependent endoribonuclease activity. Nsp16 is a 2’-O-ribose methyltransferase ( Naqvi et al., 2020 ). One study shows that there are some NSP-mediated effects on splicing, translation, and protein trafficking to inhibit host defenses. Upon SARS-CoV-2 infection, NSP16 binds mRNA recognition domains of the U1 and U2 snRNAs to suppress mRNA splicing. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome to interfere with the translation of mRNA. NSP8 and NSP9 binds to the 7SL RNA which locates at the Signal Recognition Particle to disrupt protein trafficking to the cell membrane ( Banerjee et al., 2020 ). Followings are some SARS-CoV-2 proteins which may potentially serve as antiviral drug targets based on their structures.

Spike Glycoprotein

The coronaviruses entry into host cells is mediated by spike glycoprotein (S protein) ( Li et al., 2003 ; Li et al., 2005 ; Li, 2016 ). The transmembrane spike glycoproteins form homotrimers that protrude from the viral surface. The spike glycoprotein is critical for the entry of the coronaviruses so it is an attractive antiviral target. S protein is composed of two functional subunits, including the S1 and S2 subunits. The S1 subunit consists of N-terminal domain (NTD) and receptor binding domain (RBD). The function of S1 subunit is bind to the receptor on host cell. S2 subunit contains fusion peptide (FP), heptad repeat 1 (HR1), central helix (CH), connector domain (CD), heptad repeat 2 (HR2), transmembrane domain (TM), and cytoplasmic tail (CT) ( Figure 1A ). The function of S2 subunit is to fuse the membranes of viruses and host cells. The cleavage site at the border between the S1 and S2 subunits is called S1/S2 protease cleavage site. For all the coronaviruses, host proteases cleave the spike glycoprotein at the S2’ cleavage site to activate the proteins which is critical to fuse the membranes of viruses and host cells through irreversible conformational changes. N-linked glycans are critical for proper folding, neutralizing antibodies, and decorating the spike protein trimers extensively ( Walls et al., 2020 ; Wrapp et al., 2020 ).

(A) Schematic of SARS-CoV-2 spike protein primary structure. Different domains are shown by different colors. SS, single sequence; NTD, N-terminal domain; RBD, receptor-binding domain; SD1, subdomain 1; SD2, subdomain 2; S1/S2, S1/S2 protease cleavage site; S2’, S2’ protease cleavage site; FP, fusion peptide; HR1, heptad repeat 1; CH, central helix; CD, connector domain; HR2, heptad repeat 2; TM, transmembrane domain; CT, cytoplasmic tail. The protease cleavage site is indicated by arrows. (B) Cryo-EM structure of the SARS-CoV-2 spike protein. The closed state (PDB: 6VXX) of the SARS-CoV-2 S glycoprotein (left) the open state (PDB: 6VYB) of the SARS-CoV-2 S glycoprotein (right).

Overall, the structure of SARS-CoV-2 S protein resembles the closely related SARS-CoV S protein. In the prefusion conformation, S1 and S2 subunits remain non-covalently bound. Different kinds of coronaviruses utilize special domains in the S1 subunit to recognize different entry receptors. In the case of SARS-CoV and SARS-CoV-2, to enter host cells, they recognize the receptor angiotensin-converting enzyme 2 (ACE2) on host cells via the receptor binding domain (RBD). The S protein has two forms of structure, including the closed state and the open state ( Figure 1B ). In the closed state, the three recognition motifs do not protrude from the interface formed by three spike protein protomers. In the open state, the RBD is in the “up” conformation. The open state is necessary for the fusion of the SARS-CoV-2 and the host cell membranes, thereby facilitating SARS-CoV-2 to enter the host cells ( Walls et al., 2020 ).

HR1 and HR2

The six-helical bundle (6-HB) is formed by HR1 and HR2 and is critical for membrane fusion which is dominated by the spike protein of SARS-CoV or SARS-CoV-2, making HR1 and HR2 an attractive drug target ( Liu et al., 2004 ; Xia et al., 2020b ). The difference between the 6-HB of SARS-CoV-2 and SARS-CoV may stabilize 6-HB conformation of SARS-CoV-2 and enhance the interactions between HR1 and HR2, resulting in the increased infectivity of SARS-CoV-2. The HR1-L6-HR2 complex contains most parts of HR1 and HR2 domain and a linker ( Xia et al., 2020a ). This fusion protein exhibits a rod-like shape and it is the standard structure of 6-HB. Three HR1 domains come together to form a spiral coil trimer in a parallel manner. Three HR2 domains are entwined around the coiled-coil center in an antiparallel manner which is mainly mediated by hydrophobic force. Hydrophobic residues on theHR2 domian binds with the hydrophobic groove formed by every two two neighboring HR1 helices. The overall 6-HB structure of SARS-CoV and SARS-CoV-2 is very similar, especially the S2 subunit ( Xia et al., 2020a ). The identity of the HR1 of SARS-CoV and SARS-CoV-2 is 96% and HR2 is 100%. There are eight distinct residues in the fusion core region of HR1 domain. In the HR1 domain of SARS-CoV, lysine 911 binds to the glutamic acid 1176 in HR2 domain through a salt bridge. As to SARS-CoV-2, the salt bridge is replaced by a strong hydrogen bond between serine 929 in HR1 and serine 1,196 in HR2. In SARS-CoV HR1, glutamine 915 has no interaction with HR2. However, as to SARS-CoV-2, there is a salt bridge between lysine 933 in HR1 and asparagine 1,192 in HR2 ( Xia et al., 2020a ). In SARS-CoV, there is a weak salt bridge between glutamic acid 918 in HR1 and arginine 1,166. However, aspartic acid 936 in the HR1 of SARS-CoV-2 binds to the arginine 1,158 through a salt bridge. In the SARS-CoV, lysine 929 binds to the glutamic acid 1,163 in the HR2 domain through a salt bridge and threonine 925 does not bind to the glutamic acid 1,163. However, serine 943 and lysine 947 in the SARS-CoV-2 bind to the glutamic acid 1,182 in HR2 through a hydrogen bond and a salt bridge. These differences may result in increased infectivity of SARS-CoV-2 ( Xia et al., 2020a ).

The Receptor Binding Domain (RBD)

The spike protein of SARS-CoV-2 contains an RBD that recognizes the receptor ACE2 specifically. RBD is a critical target for antiviral compounds and antibodies ( Letko et al., 2020 ). SARS-CoV-2 RBD includes two structural domains: the core and the external subdomains. The core subdomain is highly conserved. It is composed of five β strands arranged in antiparallel manner and a disulfide bond between two β strands. The external subdomain is mainly dominated by the loop which is stabilized by the disulfide bond ( Wang Q. et al., 2020 ). The SARS-CoV-2 RBD core consists of five β sheets arranged in antiparallel manner and connected by loops and short helices. Between the antiparallel β4 and β7 strands is the receptor-binding motif (RBM) which consists of loops and α helices, as well as short β5 and β6 strands. RBM contains most binding sites for SARS-CoV-2 and ACE2. Eight of the nine Cys residues in the RBD form four pairs of disulfide bonds. Three disulfide bonds are in the core of RBD, enhancing the stabilization of the β sheet (C336-C361, C379-C432, and C391-C525). With respect to the remaining disulfide bond (C480-C488), it promotes the connections between the loops in RBM. The peptidase domain in the N-terminal of ACE2 contains the binding site, which is formed by two lobes of RBM and ACE2. RBM binds to the small lobe of the ACE2 on the bottom side. The surface of RBM is slightly concave inward to make room for ACE2 ( Lan et al., 2020 ).

One study obtained a 3.5 Å-resolution structure of spike protein trimer with one RBD in the in the “up” conformation (receptor-accessible state). Receptor binding destabilizes the prefusion structure, triggered by this process, the S1 subunit dissociates and the S2 subunit refolds into a stable postfusion conformation, which has been captured in SARS-CoV. RBD goes through conformational transitions like a hinge, leading to the hide or exposure of the determinants of the spike protein to engage a host cell receptor. This process will form the following two states: “down” conformation and “up” conformation. In the “down” conformation, SARS-CoV-2 could not recognize the ACE2 on the host cells. The structure of SARS-CoV-2 is highly similar with SARS-CoV. One of the larger differences is in the down conformation, SARS-CoV RBD packs tightly against the NTD of the neighboring protomer, while the angle of SARS-CoV-2 RBD is near to the central cavity of the spike protein trimer. When aligned the individual structural domains corresponding to SARS-CoV-2 and SARS-CoV, highly similar structures were observed ( Wrapp et al., 2020 ). The overall structure of SARS-CoV-2 RBM is also nearly identical to that identified in previous studies, with only one observed difference on the distal end ( Lan et al., 2020 ).

RBD-ACE2 Complex

It is important to understand the receptor recognition mechanism of the SARS-CoV-2, which determines the infectivity, host range, and pathogenesis of the virus. Both SARS-CoV-2 and SARS-CoV recognize the ACE2 in humans ( Li et al., 2003 ; Li et al., 2005 ; Sia et al., 2020 ). The crystal structure of SARS-CoV-2 RBD bound with ACE2 has been determined ( Figure 2A ). The overall combination mode of SARS-CoV-2 RBD-ACE2 complex is highly similar with that of the identified SARS-CoV RBD-ACE2 complex in previous study. Seventeen of the 20 residues of the ACE2 interacting with the RBD of SARS-CoV and SARS-CoV-2 are the same.

(A) The overall structure of SARS-CoV-2 RBD bound with ACE2. ACE2 is colored cyan, SARS-CoV-2 RBD core is colored green (PDB: 6M0J). (B) Different interactions between SARS-CoV-2 RBD/ACE2 (PDB: 6M0J) and SARS-CoV RBD/ACE2 (PDB: 2AJF) that contribute to binding affinity difference. ACE2 is colored cyan. The RBD of SARS-CoV-2 is green, and the RBD of SARS-CoV is orange. Hydrogen bond between Q493 and E35 is represented by dash lines. Salt-bridge between ACE2 D30 and SARS-CoV-2 K417 is represented by dash lines.

However, there are subtle distinct ACE2 interactions which lead to the variation in binding affinity between SARS-CoV-2 and SARS-CoV RBD to ACE2. The affinity between ACE2 and SARS-CoV-2 is higher than the affinity between ACE2 and SARS-CoV. At the F486/L472 position, SARS-CoV-2 F486 interacts with ACE2 Q24, L79, M82, and Y83, and SARS-CoV L472 only interacts with ACE2 L79 and M82. At the Q493/N479 position, SARS-CoV-2 Q493 interacts with ACE2 K31, E35, and H34. There is a hydrogen bond between Q493 and E35. SARS-CoV N479 only interacts with ACE2 H34. Outside SARS-CoV-2 RBM, there is a salt bridge between ACE2 D30 and SARS-CoV-2 K417. However, the SARS-CoV V404 failed to participate in ACE2 binding ( Lan et al., 2020 ) ( Figure 2B ).

Another study shows the crystal structure of chimeric SARS-CoV-2 RBD-ACE2 complex. The constructed chimeric RBD which contains the RBM of SARS-CoV-2 as the function-related unit and the SARS-CoV RBD core as the crystallization scaffold could facilitate crystallization. The side loop from SARS-CoV-2 (away from the main binding interface) maintains a salt bridge between RBD R426 and ACE2 E329. This side loop could further facilitate crystallization. The structure of chimeric RBD-ACE2 complex is highly similar with the wild-type RBD-ACE2 complex as introduced above, especially in the RBM region. SARS-CoV-2 RBM forms a surface which is gently concave, binding to the claw-like structure on the exposed outer surface of ACE2. There is a N-O bridge between R439 of the chimeric RBD and E329 of ACE2. The N-O bridge is non-natural, resulting from the SARS-CoV-based chimaera. The binding affinity between chimeric RBD and ACE2 is higher than the binding affinity between wild-type SARS-CoV-2 RBD and ACE2. It is obvious that the ACE2-binding affinity of SARS-CoV RBD is lower than SARS-CoV-2 and chimeric RBDs ( Shang et al., 2020 ).

Furin Cleavage Site of the Spike Protein

The S1/S2 boundary of SARS-CoV-2 spike protein constitutes the cleavage site for the subtilisin-like host cell protease furin, which sets SARS-CoV-2 S apart from SARS-CoV S. The furin cleavage site includes four residues (P681, R682, R683, and A684) and is located at the boundary between the S1 and S2 subunit. Functionally, R682, R683, A684, and R685 constitute the minimal polybasic furin cleavage site, RXYR, where X or Y is a positively charged arginine or lysine ( Li, 2020 ). Such polybasic cleavage sites are not present in SARS-CoV and SARS-CoV-related group 2b betacoronaviruses found in humans, which may contribute to the high virulence of SARS-CoV-2 as a result of furin proteases required for proteolytic activation of S are ubiquitously expressed in humans, providing expanded tissue tropism and pathogenesis ( Sternberg and Naujokat, 2020 ).

Additionally, a study has generated a SARS-CoV-2 mutant virus lacking the furin cleavage site (δPRRA) in the spike protein. The mutant virus had reduced spike protein processing in Vero E6 cells as compared to wild type SARS-CoV-2 virus. The mutant virus also had reduced replication in Calu3 human respiratory cells and had attenuated disease in a hamster pathogenesis model. These results showed an important role of the furin cleavage site in SARS-CoV-2 replication and pathogenesis ( Johnson et al., 2020 ).

The RNA-Dependent RNA Polymerase (RdRp)

The replication of SARS-CoV-2 is dominated by a replication/transcription complex which contains several subunits. The complex is composed of viral non-structural proteins (nsp) and the core of the complex is the RdRp in nsp12. The functions of the nsp12 require accessory factors, including nsp7 and nsp8. Nsp12 alone has little activity. The presence of nsp7 and nsp8 significantly increased the combination of nsp12 and template-primer RNA. The crystal structure of nsp12-nsp7-nsp8 complex has been identified ( Figure 3A ). RNA-dependent RNA polymerase, which catalyzes the synthesis of viral RNA, is a critical composition of coronavirus replication/transcription. RdRp is an important antiviral drug target. The structures on the SARS-CoV-2 nsp12 contain a nidovirus-unique N-terminal extension domain which adopts a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) structure and a “right hand” RNA-dependent RNA polymerase domain in the C-terminal. These two domains are connected by an interface domain. A unique β-hairpin is observed in the N-terminal extension domain. The β-hairpin forms close contacts to stabilize the overall structure. The RNA-dependent RNA polymerase domain contains three subdomains: a fingers subdomain, a palm subdomain, and a thumb subdomain. The β-hairpin structure inserts into the clamping groove formed by the palm subdomain and the NiRAN domain. In the plam domain, polymerase motifs A−G which is highly conserved form the active site chamber of SARS-CoV-2 RdRp domain. The RdRp motifs mediate template-directed RNA synthesis in a central cavity through four positively charged solvent-accessible paths, including template entry path, primer entry path, the NTP entry channel, and the nascent strand exit path ( Gao Y. et al., 2020 ). A recent study shows the cryo-electron microscopic structure of the nsp12-nsp7-nsp8 complex in active form ( Yin et al., 2020 ) ( Figure 3B ).

(A) The structure of nsp12-nsp7-nsp8 complex. Color marks: nsp7, magenta; nsp8-1 and nsp8-2, grey; β-hairpin, cyan; NiRAN, yellow; the interface, orange; the fingers domain, blue; the palm domain, red; the thumb domain, green. (PDB: 6M71) (B) The structure of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) in active form. The nsp12-nsp7-nsp8 complex bound to the template-primer RNA. (PDB: 7BV2).

When added a minimal RNA hairpin substrate, the complex nsp12-nsp7-nsp8 exhibited RNA-dependent RNA extension activity. The structure of RdRp-RNA complex shows nsp12-nsp7-nsp8 complex engaged with more than two turns of duplex RNA. The RdRp-RNA structure is similar to that of the free enzyme with some unique characteristics. Compared with free enzyme, the RdRp-RNA complex contains an extended protein region in nsp8 and a protruding RNA. The subunit nsp12 binds with the first turn of RNA between its thumb subdomains and fingers subdomains. The palm subdomain contains the active site which is formed by five nsp12 motifs A−E. Motif C interacts with the 3’ end of RNA and includes the aspartic acid 760 and 761. The nsp12 motifs F and G lies in the fingers subdomain and have the function of positioning the RNA template. As the RNA duplex leaves the cleft of the RdRp, it forms a second helical turn, protruding from the surface of nsp12. No structural factors in the RdRp will limit RNA duplex extension. Between the α-helical extensions is the RNA duplex. The N-terminal regions, which are located in the two nsp8 subunits and are highly conserved, form the α-helical extensions. These nsp8 extensions use the positively charged residues to interact with the RNA backbones. The nsp8 could function as the “sliding poles”, sliding along the protruding RNA to prevent RdRp from dissociating prematurely during replication. The triphosphate-binding site is conserved. Residues D623, S682, and N691 are likely to interacts with the 2’-OH group of the triphosphate (NTP), making the RdRp special for the synthesis of RNA instead of DNA ( Hillen et al., 2020 ).

The Main Protease

The main protease (M pro ) of SARS-CoV-2 plays a pivotal role in mediating the replication and transcription of viral gene. M pro hydrolyzes the polyprotein at least eleven conserved sites and begins with cleaving the pp1a and pp1b of M pro . Considering the absence of closely related homologues in humans, together with the functional importance of the main protease in the life cycle of the virus, the main protease is an attractive antiviral target. The crystallographic symmetry shows that M pro forms a homodimer (protomer A and protomer B). Each protomer contains three subdomains, namely domain I, domain II, and domain III. A long loop connects domain II and domain III. The cleft between domain I and domain II lies the substrate-binding pocket, which features the catalytic dyad residues His41 and Cys145 ( Jin et al., 2020a ). As to all the coronaviruses, the active sites of M pro are highly conserved and consists of four sites: S1’, S1, S2, and S4. In the S1’ site, the thiol of a cysteine anchors inhibitors by a covalent linkage. For inhibitors, the covalent linkage is critical to maintain its antiviral activity ( Yang et al., 2005 ).

The spike protein is critical in the process of SARS-CoV-2 invading host cells. The main protease and RdRp have important functions in the replication of SARS-CoV-2. As a result, the spike protein, main protease, and RdRp are important anti-SARS-CoV-2 drug targets, providing ideas for the development of antibodies, drugs, and vaccines.

Structure-Based Antibodies Against SARS-CoV-2

Recently, the study indicates that SARS-CoV-2 invades host cells through a new route: CD147-spike protein, through which spike protein bound to CD147, a transmembrane glycoprotein belongs to the immunoglobulin superfamily, thereby mediating the invasion of SARS-CoV-2. Meplazumab is an anti-CD147 humanized antibody. It could block CD147 and significantly prevent the SARS-CoV-2 from entering host cells. BIOcore experiment shows that the affinity constant between CD147 and RBD is 1.85×10 -7 M. Unlike ACE2, CD147 is highly expressed in inflamed tissues, pathogen infected cells, and tumor tissues. It has low cross-reaction with normal cells. As a result, CD147 targeted drugs are safe and reliable ( Wang K. et al., 2020 ).

Monoclonal Antibody 4A8

One study isolated monoclonal antibodies (MAbs) from ten SARS-CoV-2 infected patients in recovery period. Among these antibodies, MAb 4A8, exhibits high neutralization activities against SARS-CoV-2. The crystal structure of spike protein-4A8 complex at 3.1 Å resolution shows that three 4A8 monoclonal antibodies binds the N-terminal domain (NTD) of the spike protein trimer. Each of the 4A8 monoclonal antibody interacts with one N-terminal domain (NTD) of the spike protein.

The crystal structure of spike protein-4A8 complex at 3.1 Å resolution shows that each one of the three 4A8 monoclonal antibodies binds to one N-terminal domain (NTD) of the spike protein trimer. The asymmertric conformation of the trimeric spike protein exhibits one of three RBD in “up” conformation and two RBDs in “down” conformation. The interface between 4A8 and the corresponding NTD is identical. Among the five new constructed loops for NTD which are designed as N1 which are designated as N1−N5, N3 and N5 loops dominate the interactions with 4A8. Three complementarity-determining regions (CDRs) which are designated as CDR1, CDR2, and CDR3 on the heavy chain of 4A8 binds with NTD. R246 on the N5 loop interacts with the Y27 and E31 of 4A8 on the CDR1. K150 and K147 on the N3 loop form salt bridges with E54 and E72 of 4A8 respectively. There are hydrogen bonds between K150 and 4A8-Y111, H146 and 4A8-T30 ( Chi et al., 2020 ).

Monoclonal Antibody 47D11

A human monoclonal antibody (mAb) 47D11 is found to potently block SARS-CoV-2 infection. The target of 47D11 is the RBD and spike ectodomain (S ecto ) of the SARS-CoV-2 spike protein. The 47D11 binds to the RBD of SARS-CoV and SARS-CoV-2 with similar affinity constant. However, the binding affinity between 47D11 and SARS-CoV-2 S ecto was lower than that of SARS-CoV. The binding of 47D11 to SARS-CoV-RBD and SARS-CoV-2-RBD did not compete with the binding of 47D11 to the ACE2 receptor on the cell surface ( Wang C. et al., 2020 ). Despite the relatively high degree of structural similarity between the SARS-CoV RBD and the SARS-CoV-2 RBD, when using the three reported SARS-CoV RBD-directed monoclonal antibodies which have a strong binding to the SARS-CoV RBD, there is no detectable binding for any of the three mABs (S230, m396, 80R) at the tested concentration. Because of the different antigenicity, SARS-directed mAbs have no absolute cross reactions with SARS-CoV-2-directed mAbs ( Wrapp et al., 2020 ).

Monoclonal Antibody CR3022

The SARS-CoV-specific antibody, which was discovered in the plasma of a SARS-infected patient in recovery period, CR3022, could also bind with the RBD of SARS-CoV-2 potently. After saturating the streptavidin biosensors which labelled with biotinylated SARS-CoV-2 RBD, followed by the mixture of CR3022 and ACE2, the results indicated that the binding sites of CR3022 on RBD is different from ACE2. The mixture of CR3022 and CR3014 (a potent SARS-CoV-specific neutralizing antibody) neutralized SARS-CoV-2 in a collaborative way, with different epitopes on RBD. In conclusion, CR3022 has the potential to function as one kind of therapeutics, alone or with other neutralizing antibodies ( Tian et al., 2020 ). The crystal structure of CR3022-RBD complex has been determined ( Figure 4A ). The light chain, heavy chain, and six CDR loops (H1, H2, H3, L1, L2, and L3) of CR3022 are used to interact with the RBD of SARS-CoV-2.

The crystal structure of the antibody-RBD/spike protein complex. (A) Crystal structure of CR3022 in complex with SARS-CoV-2 RBD. CR3022 heavy chain is colored in cyan and light chain in yellow. The SARS-CoV-2 RBD in colored in magenta (PDB: 6W41). (B) The crystal structure of B38/SARS-CoV-2 RBD. The heavy chain of B38 is colored magenta and the light chain is colored green. The RBD is colored cyan (PDB: 7BZ5). (C) The crystal structure of CB6-Fab/SARS-CoV-2-RBD. The heavy chain of CB6 is colored magenta and the light chain of CB6 is colored cyan. The SARS-CoV-2-RBD is colored green (PDB: 7C01). (D) The crystal structure of P2B-2F6 Fab/SARS-CoV-2 RBD complex. The light chain of P2B-2F6 Fab is colored yellow and the heavy chain is colored cyan. The SARS-CoV-2 RBD is colored magenta (PDB: 7BWJ). (E) The crystal structure of the complex of SARS-CoV-2 spike RBD bound to Fab fragments of REGN10933 and REGN10987. REGN10933 heavy and light chains are cyan and green, and REGN10987 heavy and light chains are magenta and yellow, respectively (PDB: 6XDG). (F) The crystal structure of BD-23 Fab/spike protein trimer complex. The light chain of BD-23 Fab is colored blue and the heavy chain is colored magenta. The three protomers in the spike protein trimer are colored cyan (A) , green (B) , and yellow (C) (PDB: 7BYR).

CR3022’s recognition of SARS-CoV-2 is mainly mediated by hydrophobic interactions. As to SARS-CoV and SARS-CoV-2, 24 of 28 residues buried by antibody CR3022 are the same, which is the cause of the cross-reactivity of CR3022. Although the high similarities of sequence, the affinity between CR3022 and SARS-CoV RBD is much higher than the affinity between CR3022 and SARS-CoV-2 RBD, likely resulting from the non-conserved residues in the epitope. Only when the RBD is in the “up” conformation, the epitope of CR3022 is exposed. If only one RBD on the trimeric S protein is in the “up” conformation, there would exist some clashes between CR3022 and RBD to hinder the bind. First, the variable region of CR3022 collides with S2 subunit of RBD, as well as the adjacent RBD in “down” conformation. Second, the constant region of CR3022 collides with NTD. When the targeted-RBD are in the double-“up” conformation (at least two) with a slight rotation, the binding epitope of the RBD can be accessed by CR3022 and all the clashes can be resolved ( Yuan et al., 2020 ).

Monoclonal Antibodies B38 and H4

The monoclonal antibodies B38 and H4 isolated from a convalescent patient display neutralization ability. The crystal structure of B38-RBD complex has been identified ( Figure 4B ). B38 and H4 are able to hinder the binding between SARS-CoV-2 RBD and cellular receptor ACE2. The epitopes of B38 and H4 on the RBD are different. As a result, B38 and H4 has the potential to function as the noncompeting monoclonal antibody pair to treat COVID-19. In infected lungs, B38 and H4 can reduce virus titers. The crystal structures of RBD-B38 indicates that two CDRs on the light chain and all the three CDRs on the heavy chain of CR3022 interacts with RBD. A total of 21 amino acids in the RBD binds with the heavy chain and 15 residues with the light chain. Among the 36 residues, only 15 residues are conserved between SARS-CoV and SARS-CoV-2. Hydrophilic interactions mediate most of the contacts between B38 and RBD. Water molecules play a significant role in the binding between SARS-CoV-2 RBD and B38. The comparison of RBD/B38-Fab complex and RBD/hACE2 complex shows no obvious conformational changes and 18 of 21 amino acids on the RBD are conserved between B38 and ACE2. This explains why antibody B38 blocks SARS-CoV-2 from binding to receptor ACE2 ( Wu et al., 2020b ).

Monoclonal Antibodies CA1 and CB6

Two human monoclonal antibodies CA1 and CB6 could potently neutralize the SARS-CoV-2 in vitro . Particularly, CB6 could reduce lung damage and inhibit the titer of SARS-CoV-2 in rhesus monkeys, thereby having the potential to treat and prevent SARS-CoV-2 infection. The crystal structure of CB6-Fab/SARS-CoV-2-RBD complex indicates that CB6 binds to the RBD of SARS-CoV-2 ( Figure 4C ). CDR1, CDR2, and CDR3 loops in the CB6 V H dominate the interaction between the CB6 and SARS-CoV-2-RBD, forming concentrated hydrophobic interactions and polar contacts. CB6 light chain has limited interactions with SARS-CoV-2-RBD, with only one hydrogen bond between Y505 and Y92. The superimposition of CB6/SARS-CoV-2-RBD complex and hACE2/SARS-CoV2-RBD complex indicated the steric competition between hACE2 and CB6 for RBD binding. The steric hindrance caused by CB6 is dominated by both the light chain and heavy chain of CB6, thus resulting in structure clashes with the SARS-CoV-2-RBD. CB6 and hACE2 have many overlapping binding sites on the RBD. In conclusion, steric hindrance caused by the V H and V L of CB6 and the overlapped binding areas inhibit the binding of SARS-CoV-RBD and hACE2 ( Shi R. et al., 2020 ).

Monoclonal Antibody P2B-2F6

Total 206 kinds of RBD-specific monoclonal antibodies have been isolated from the B cells of 8 COVID-19 patients. The most potent neutralizing antibodies are P2C-1F11, P2B-2F6, and P2C-1A3. The crystal structure of P2B-2F6/SARS-CoV-2 RBD complex has been determined at 2.85 Å resolution ( Figure 4D ). The interactions between P28-2F6 and the SARS-CoV-2 RBD is dominated by the heavy chain of P28-2F6. The paratope contains 3 light chain residues and 14 heavy chain residues. All the 12 epitopes residues are in the RBM, including lysine 444, glycine 446 and 447, asparagine 448, tyrosine 449, asparagine 450, leucine 452, valine 483, glutamic acid 484, glycine 485, phenylalanine 490, and serine 494. At the binding interface, there are hydrophobic interactions between P2B-2F6 and SARS-CoV-2 RBD residues Y449, L452, and F490, facilitating P2B-2F6 attachment. Hydrophilic interactions also exit at the binding interface. Structural superimposition of SARS-CoV-2 RBD/ACE2 complex and SARS-CoV-2 RBD/P2B-2F6 complex shows that the light chain of P2B-2F6 clashes with ACE2 residues aspartic acid 67, lysine 68, alanine 71, lysine 74, glutamic acid 110, and lysine 114, inhibiting the binding of ACE2 and RBD. The residues in RBD recognized by both P2B-2F6 and ACE2 are Y449 and G446. Compared with the binding affinity between ACE2 and RDB, the binding affinity between P2B-2F6 and RBD is higher. P2B-2F6 Fab could connect with both the “up” and “down” conformations of the RBDs of the trimer spike protein, while ACE2 only binds the “up” conformation of RBD ( Ju et al., 2020 ).

Antibody Cocktail: REGN10987 and REGN10933

One study used both genetically modified mice and B cells from SARS-CoV-2 convalescent patients to collect monoclonal antibodies. It has been identified that REGN10987 and REGN10933 are a pair of highly potent individual antibodies. The epitope of REGN10933 is located at the top of the RBD while the epitope of REGN10987 is located at the side of the RBD. They can bind to the RBD of SARS-CoV-2 simultaneously without competition. As a result, REGN10987 and REGN10933 can be paired in a therapeutic antibody cocktail. The bind of REGN10933 to RBD overlap the binding site for ACE2 extensively. However, the binding of REGN10987 has no or little overlap with the binding site of ACE2. The crystal structure has been identified ( Hansen et al., 2020 ) ( Figure 4E ).

Monoclonal Antibody BD-23

High-throughput single-cell RNA and VDJ sequencing were used to identify SARS-CoV-2 neutralizing antibodies from the B cells of 60 convalescent patients and 14 antibodies with strong neutralization ability were discovered, including the neutralizing antibody BD-23. The crystal structure of BD-23-Fab/spike protein at 3.8 Å resolution has been solved ( Figure 4F ). The spike adopts an asymmetric conformation. Two RBDs of the spike protein trimer adopt “down” conformation and the other adopts “up” conformation. Structural superimposition of SARS-CoV-2 RBD/ACE2 complex and SARS-CoV-2 RBD/BD-23 complex shows that BD-23 could clash with ACE2 to inhibit the RBD-ACE2 binding, endowing BD-23 with the SARS-CoV-2 neutralizing ability ( Cao et al., 2020 ).

A variety of other antibodies are found targeting the spike protein of the SARS-CoV-2. Antibody n3130 and n3088 target the S RBD and S1 subunit with the affinity of 55.4 nM ( Wu et al., 2020a ). Antibody S309 comes from B cells of SARS rehabilitation patients. It has cross-reaction with SARS-CoV and the affinity with its target S B is 0.1 nM. The crystal structure of S309 has been identified ( Pinto et al., 2020 ). Antibodies n3103, n3088, and S309 do not block the binding of SARS-CoV-2 with its receptor ACE2. Horse F(ab’)2 comes from horse serum immunized with RBD and the affinity between F(ab’)2 and RBD is 0.76 nM ( Pan et al., 2020 ).

Structure-Based SARS-CoV-2 Inhibitors

Currently, some small-molecule compounds have been developed which showed inhibitory effects on the SARS-CoV-2 infection, as described below.

Remdesivir is an adenosine analogue and is a potent inhibitor of RdRp. Remdesivir could potently inhibit the replication of SARS-CoV-2 in vitro . Remdesivir shows broad-spectrum antiviral effects against RNA virus infection in cultured cells, nonhuman primate models, and mice. As an adenosine analogue, remdesivir functions after virus entry, via incorporating into nascent viral RNA to terminate the replication before the RNA become mature ( Gurwitz, 2020 ). Remdesivir is a kind of prodrug. In target cells, it would transform into the triphosphate form (RTP) and become active ( Siegel et al., 2017 ). Like other nucleotide analog prodrugs, remdesivir inhibits the RdRp activity through covalently binds the primer strand to terminate RNA chain. Upon adding ATP, the nsp12-nsp7-nsp8 complex exhibits the function of RNA polymerase. However, with the addition of the active triphosphate form of remdesivir (RTP), the RNA polymerization activity would be significantly inhibited. The structure of the apo RdRp is composed of nsp12, nsp7, and nsp8. Besides, the template-RTP RdRp complex is composed of a 14-base RNA in the template strand as well as 11-base RNA in the primer strand. Of note, the remdesivir is in the monophosphate form (RMP) in the complex. The RMP is covalently linked to the primer strand, three magnesium ions, and a pyrophosphate. The three magnesium ions locate near the active site and promote catalysis. The RMP locates in the catalytic active site center. The catalytic active site is composed of seven motifs. There are base-stacking interactions between RMP and the base of the primer strand in the upstream. Hydrogen bonds also exists between RMP and the uridine base of the template strand. There are also interactions between RMP and side chains (K545 and R555). Twenty-nine residues from nsp12 participate the binding of the RNA directly. No residue from nsp7 or nsp8 mediates the RNA interactions ( Yin et al., 2020 ).

Similar to remdesivir, favipiravir is also an inhibitor of the RdRp. The structure of favipiravir resembles the endogenous guanine. Clinical trial demonstrated that favipiravir had little side effect as the first anti-SARS-CoV-2 compound conducted in China ( Furuta et al., 2017 ; Tu et al., 2020 ).

A mechanism-based inhibitor, N3, which was identified by the drug design aided by computer, could fit inside the substrate-binding pocket of the main protein and is a potent irreversible inhibitor of the main protein. Two of the Mpro-N3 complex associate to form a dimer (the two complexes are named protomer A and protomer B, respectively). Each protomer contains three domains which are designated as domain I−III. Both domain I and domain II have a β-barrel structure arranged in antiparallel manner. Domain III has five α-helices which associate to form a globular cluster structure in antiparallel manner. Domain III connects to domain II with a long loop. The cleft between domain I and domain II contains the substrate binding site. The backbone atoms of the compound N3 form an antiparallel sheet with residues 189–191 of the loop that connects domain II and domain III on one side, and with residues 164–168 of the long strand (residues 155–168) on the other ( Jin et al., 2020a ) ( Figure 5A ).

The crystal structure of N3 and its inhibitors. (A) The crystal structure of N3-main protease complex. The main protease is colored brightorange. N3 is colored green (PDB: 6LU7). (B) The crystal structure of 11a-main protease complex. The main protease is colored brightorange, 11a is blue (PDB: 6LZE). (C) The crystal structure of 11b-main protease complex. The main protease is brightorange, 11b is red (PDB: 6M0K). (D) The crystal structure of Carmofur-main protease complex. The main protease is brightorange, carmofur is cyan (PDB: 7BUY).

11a and 11b

Two compounds, namely 11a and 11b which target the M pro , exhibit excellent inhibitory effects on SARS-CoV-2 infection in vitro . The inhibitory activity of 11a and 11b at 1 µM is 100 and 96%. In vivo, the 11a and 11b exhibit good pharmacokinetics (PK) properties. Of note, 11a showed low toxicity as well. The -CHO group of 11a and 11b bond to the cysteine 145 of M pro covalently. Different parts of 11a (designated as P1’, P1, P2, and P3) fits into different parts of the substrate-binding site. The (S)-γ-lactam ring of 11a at P1 inserts into the S1 site. The cyclohexyl moiety of 11a at P2 fits into the S2 site. At the part P3 of 11a, the indole group is exposed to the S4 site (in the solvent). The oxygen atom of -CHO forms a hydrogen bond with the cysteine 145 in the S1’ site. In addition, many water molecules (designated as W1−W6) are critical for binding 11a. The SARS-CoV-2 M pro -11b complex is similar to the SARS-CoV-2 M pro -11a complex and the 11a and 11b exhibit similar inhibitor binding mode ( Dai W. et al., 2020 ) ( Figures 5B, C ).

Camostat Mesylate

TMPRSS2 and TMPRSS4 are two mucosa-specific serine proteases which facilitate the fusogenic activity of SARS-CoV-2 spike protein and facilitate the virus to enter host cells ( Zang et al., 2020 ). SARS-CoV-2 employs the TMPRSS2 in cells to prime the spike protein. TMPRSS2 activity is critical for the spread of SARS-CoV-2 as well as the pathogenesis in the infected host. Therefore, TMPRSS2 is a potential antiviral target. The spectrum of cell lines mediated entry by the S protein of SARS-CoV-2 and SARS-CoV are similar. Camostat mesylate, a clinical TMPRSS2 inhibitor, can partially block SARS-CoV-2 spike-driven entry into lung cells. In addition, camostat mesylate exhibits potent inhibit activity on SARS-CoV, SARS-CoV-2, and MERS-CoV, inhibiting them from entering lung cell line Calu-3, without cytotoxicity. In conclusion, camostat mesylate has the potential to treat and prevent COVID-19 ( Hoffmann et al., 2020 ).

The antineoplastic drug carmofur can inhibit the main protease (M pro ) of SARS-CoV-2. The crystal structure of carmofur-main protease complex has been solved. Carmofur inhibits the activity of SARS-CoV-2 main protein in vitro and the half-maximum inhibitory concentration (IC50) is 1.82 μM. Carmofur is an approved antineoplastic agent used for colorectal cancer. It is a derivative of 5-fluoroyracil (5-FU). The molecular details of how carmofur inhibits the activity of SARS-CoV-2 main protein have not been resolved. One study showed the crystal structure of SARS-CoV-2 M pro -carmofur complex. The electron density figure indicates that the fatty acid moiety (C 7 H 14 NO) of carmofur links with the Sγ atom of SARS-CoV-2 main protein catalytic residue Cys145 covalently. The electrophilic carbonyl group of carmofur is attacked by the sulfhydryl group of Cys145. This process modifies the Cys145 covalently and releases the 5-FU motif. Notably, numerous hydrogen bonds and hydrophobic interactions stabilize the inhibitor carmofur. The fatty acid tail of carmofur (an extended conformation) inserts into the S2 subunit of SARS-CoV-2. Most of the hydrophobic interactions are contributed by His41, Met165, and Met49 in the side chain ( Jin et al., 2020b ) ( Figure 5D ).

Lipopeptide EK1C4

The complex (6-HB) formed by the HR1 and HR2 of the SARS-CoV-2 S protein could facilitate the infection of the viruses ( Xia et al., 2020b ). EK1 is one kind of coronavirus fusion inhibitor and has an inhibitory effect on various coronaviruses. It targets the HR1 of the S protein of human coronavirus and has been proved to effectively inhibit the infection of five HCoVs, including SARS-CoV and MERS-CoV. Peptide EK1 could intervene the formation of viral 6-HB ( Xia et al., 2020a ). A recent study shows that the peptide EK1 could also inhibit the membrane fusion mediated by SARS-CoV-2 spike protein as well as SARS-CoV-2 pseudovirus infection in a dose-dependent manner ( Xia et al., 2020a ; Xia et al., 2020b ). EK1C is constructed by covalently attaching the cholesterol acid to the C-terminal of EK1 sequence. It is noteworthy that the lipopeptide EK1C4 has the strongest inhibitory effect on the membrane fusion which is mediated by the spike protein, with IC50 of 4.3 nM. However, the IC50 of EK1 is 409.3 nM. EK1C4 could also potently inhibit the infection caused by live coronavirus in vitro with little, or even no, toxic effect. In conclusion, EK1C4 has the potential to be used for the treatment and prevention of COVID-19 ( Xia et al., 2020a ).

Vaccines of SARS-CoV-2

It is urgent to develop effective and safe vaccines to control the new occurrence of COVID-19 and to reduce SARS-CoV-2-infection-related morbidity and mortality ( Amanat and Krammer, 2020 ). Chinese Health Commission announced that more than five kinds of vaccines are currently developed for COVID-19 in China, including subunit protein vaccine, nucleic acid vaccine, inactivated vaccine, adenoviral vector vaccine, and influenza viral vector vaccine ( Lu, 2020 ; Sun J. et al., 2020 ). As of October 17, 2020, there are 177 vaccine candidates for COVID-19 and 54 are in human trials in the world ( https://biorender.com/covid-vaccine-tracker ). For example, the non-replicating Ad5 vectored COVID-19 vaccine produced by CanSino Biologics lnc, the mRNA-1273 COVID-19 vaccine developed by Moderna, the DNA vaccine of Inovio Pharmaceuticals, the BioNTech’s mRNA COVID-19 vaccine, the vaccine ChAdOx1 nCoV-19 of University of Oxford ( Zhu et al., 2020 ), the adenovirus serotype 26 vector-based vaccine Ad26.COV2.S, the Novavax’s protein subunit vaccine NVX-CoV2373, the Sinovac’s inactive vaccine CoronaVac, the Chulalongkorn University’s mRNA vaccine ChulaCov19, etc. ( https://biorender.com/covid-vaccine-tracker ). Currently, clinically approved vaccines are not widely available ( Hu B. et al., 2020 ). The safety and efficacy of the vaccines should be kept in mind in the efforts of vaccine development. Following are some notable SARS-CoV-2 vaccines in development.

Moderna’s mRNA-based vaccine stimulates the expression of target antigen after injection of mRNA encapsulated in nanoparticles ( Amanat and Krammer, 2020 ). The vaccine is called mRNA-1273, it is a synthetic mRNA strand, which can encode the viral spike protein that is stable before fusion. After being injected into the body intramuscularly, the vaccine mRNA-1273 could stimulate antiviral response that targets the spike protein of SARS-CoV-2 specifically. Different from conventional route of vaccine development, the lipid mRNA nanoparticle-encapsulated mRNA vaccine can be synthesized and made without the virus ( Tu et al., 2020 ). At present, mRNA-1273 has completed phase I clinical trial (ClinicalTrials.gov Identifier: NCT04283461) and phase II clinical trial. The results of the mRNA-1273 vaccine phase I clinical trial in 45 healthy adults (18–55 years old) show a strong antibody and cellular immune response in participants and no safety concerns are identified ( Jackson et al., 2020 ). Phase II clinical trial is a dose-conformation study used to evaluate the safety, reactogenicity, and immunogenicity of mRNA-1273 in healthy adults. The phase III clinical trial has started on July 27, 2020 (ClinicalTrials.gov Identifier: NCT04470427). This is a randomized, stratified study to evaluate the efficacy, immunogenicity, and safety of the vaccine in healthy adults.

Recombinant Adenovirus Type-5 (Ad5) Vectored Vaccine

The phase I clinical trial of an Ad5 vectored COVID-19 vaccine has been done in Wuhan, China. The Ad5 vectored COVID-19 vaccine targets the spike protein of SARS-CoV-2. This trial is a dose-escalation, non-randomized, open-label, and first-in-human trial. The vaccine trial had three dose groups, including 5×10¹⁰, 1×10¹¹, and 1.5×10¹¹ viral particles. A total of 108 participants who were healthy and aged between 18−60 years old were allocated to one of the three dose group and each group contains 36 participants. The vaccine is injected intramuscularly into the human body. Results indicated that participants in all the dose groups exhibited at least one adverse reaction within 7 days post-vaccination. The most reported adverse reaction at the injection site was pain. Fever and fatigue were the most common systematic symptoms, 46 and 44% of the recipients exhibited such symptoms, respectively. However, most reported adverse reactions were mild or moderate in severity. Within 28 days after vaccination, no serious adverse reactions were reported. Humoral responses against SARS-CoV-2 peaked 28 days after vaccination in participants. From 14 days after vaccination, the specific T-cell responses were notable and rapid. Results demonstrate that this vaccine is immunogenic and tolerable in healthy adults and has the potential to control the outbreak of COVID-19. However, further investigations are needed to identify the immunogenicity and safety of this vaccine ( Zhu et al., 2020 ). The phase II trial in China (NCT04341389) has started. This is a randomized, double-blinded and placebo-controlled clinical trial in healthy adults. The purpose of the study is to evaluate the safety and immunogenicity of Ad5 vectored vaccine.

In a recent study, a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc) is developed in a pilot-scale production. The target of PiCoVacc is the entire virus. The study indicated that PiCoVacc could induce neutralizing antibodies which neutralized 10 representative SARS-CoV-2 strains in mice, rats, and non-human primates, suggesting its strong potential to neutralizing the other SARS-CoV-2 strains that are circulating. Six μg per dose of the PiCoVacc could protect the macaques from SARS-CoV-2 infection completely and systematic evaluation suggests its safety ( Gao Q. et al., 2020 ).

DNA Vaccines

A recent study ( Yu J. et al., 2020 ) has produced a series of DNA vaccine candidates which express six variants of the spike protein of the SARS-CoV-2. DNA vaccines targets the spike protein of SARS-CoV-2. The candidates were evaluated in 35 rhesus macaques. At week 0 and week 3, rhesus macaques were injected 5 mg DNA vaccines intramuscularly. S-specific binding antibodies and neutralizing antibodies (NAbs) were detected after the boost immunization at week 5. Neutralizing antibody (NAb) titers in the vaccinated macaques were comparable to the Nab titers in 9 convalescent rhesus macaques and 27 convalescent patients who were infected with SARS-CoV-2. Cellular immune responses targeting the S peptides were observed in most of the vaccinated rhesus macaques at week 5. At week 6, all rhesus macaques were challenged with 1.2×10 8 VP SARS-CoV-2 intranasally and intratracheally. Compared to the control groups, lower levels of SARS-CoV-2 RNA were observed in the vaccine groups. Reduced levels of subgenomic mRNA (sgmRNA) in bronchoalveolar lavage (BAL) and nasal swabs (NS) were observed in vaccine groups. In conclusion, these DNA vaccines prevent rhesus macaques from being infected by SARS-CoV-2 and may accelerate the development of SARS-CoV-2 vaccine which are urgently needed to protect humans from SARS-CoV-2 infections.

A Universal Betacoronavirus Vaccine Against COVID-19, MERS, and SARS

The RBD of coronaviruses is an attractive vaccine target. However, RBD-based vaccines have relatively low immunogenicity. One study describes the dimeric form of MERS-CoV RBD. Compared to monomeric form, the RBD-dimer could expose double receptor-binding motifs and increase neutralizing antibody (NAb) titers significantly, so as to overcome the limitation of low immunogenicity. RBD-sc-dimer is a stable version of RBD-dimer with high vaccine efficacy. When using this strategy to design vaccines against SARS and COVID-19, 10–100-fold enhancement of Nab titers were achieved. Notably, the Nab titers caused by two-dose of RBD-sc-dimer is much higher than the RBD-sc-dimer, reaching ~4,096 ( Dai L. et al., 2020 ).

On June 23, 2020, the clinical phase III trial of the inactivated SARS-CoV-2 vaccine developed by the SINOPHARM CNBG launched officially. This is the first international clinical phase III trial of inactivated SARS-CoV-2 vaccine. The clinical phase III trial takes about half a year to evaluate the safety and effectiveness of the vaccine in a larger population.

The rapid global pandemic of SARS-CoV-2 has already posed a great threat to human health, social health system, global economy, and even the global governance, and these influences may likely continue for a longer time. We need to learn the epidemic logic of SARS-CoV-2 and study the unknown viruses carried by wild animals in nature in advance to make early warning. There may be an outbreak caused by other kinds of viruses next time except for SARS-CoV-2. Study experiences and lessons on different viruses may be referenced each other.

Sufficient understanding on the differences of structural and non-structural proteins among SARS-CoVs and other coronaviruses may help to the development of therapeutics for SARS-CoV-2 infection. The non-structural proteins of the coronaviruses which can infect humans are relatively similar with SARS-CoV-2 in structure. Except S protein, most of the structural proteins, such as E protein and M protein, showed no significant difference in protein architecture between SARS-CoV-2 and other known human CoVs. The S protein of CoVs is responsible for binding the host cell-surface receptor during host cell entry. Different CoVs recognize different cell surface receptor. For instance, MERS-CoVs recognize the dipeptidyl peptidase 4 receptor. Nevertheless, SARS-CoV and SARS-CoV-2 recognize the ACE2 receptor. This may be the reason why different CoVs have various host entry mechanism. In addition, the SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Unlike SARS-CoV, the entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD and the furin preactivation of the spike allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus.

Due to the limited knowledge about SARS-CoV-2 at present, there is no approved therapeutic drugs or vaccines available for the treatment of COVID-19. As the global epidemic worsens, effective and safe vaccines, antibodies, and specific anti-SARS-CoV-2 drugs are in urgent need. Neutralizing antibodies are expected effective for SARS-CoV-2 infection, but their costs, production scales, and covering rates are still questions. Vaccine development also faces difficulties such as timeliness and ineffectiveness due to inconsiderate vaccine design and/or virus mutation.

Unlike the vaccine which has a relatively clear mechanism and route in development, antiviral drugs with high potency and high safety may be more difficult to develop at present because of our incomplete understanding on the virus world and the host responsiveness. This may be the reason why there is no one satisfactory antiviral drug available till now. The potential in vivo toxic effect of an antiviral drug which is claimed effective in vitro may disappointingly overwhelm its pharmacological applause. New and unconventional ideas and routes of antiviral drug design and development are needed to overcome the shortcomings of the present reductionism-based drug research. In this aspect, the holism-based traditional Chinese medicine especially the Chinese medical herb formulae could be considered which are proved effective in the fight against COVID-19 in China ( Ang et al., 2020 ; Luo et al., 2020 ; Ren et al., 2020 ; Zhang et al., 2020a ; Zhong et al., 2020 ), although further mechanistic studies and large-scale clinical trials are warranted.

Recently, many countries in the world have increased their investment in the research and development of antiviral drugs, antibodies, and vaccines. Accelerating the development of vaccines is likely the current keyway to solve this global disaster. Through joint efforts around the world, people can develop effective anti-SARS-CoV-2 technologies hopefully in the near future.

Author Contributions

M-YW and RZ wrote the manuscript. L-JG and X-FG helped drew the figures. D-PW and J-MC revised the manuscript. All authors contributed to the article and approved the submitted version.

This work and related studies were supported by Shanxi “1331 Project” Key Subjects Construction (1331KSC), Applied Basic Research Program of Shanxi Province (201801D221269), Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi (STIP) (2019L0437), and the National Natural Science Foundation of China (81670313).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Biology of SARS-CoV-2

• DNA & RNA
• Pathogens & Disease

Resource Type

• Click & Learn

Description

This four-part animation series explores the biology of the virus SARS-CoV-2, which has caused a global pandemic of the disease COVID-19.

SARS-CoV-2 is part of a family of viruses called coronaviruses. The first animation, Infection , describes the structure of coronaviruses like SARS-CoV-2 and how they infect humans and replicate inside cells. The second animation, Evolution , describes how these viruses evolve and discusses positive, negative, and neutral mutations. The third animation, Detection , describes the methods used to detect active and past SARS-CoV-2 infections. The fourth animation, Vaccination , describes the different types of vaccinations for SARS-CoV-2 and how they prevent disease. These animations are also available in a YouTube playlist .

The accompanying “Student Worksheets” incorporate concepts and information from the animations. The “Version 1” worksheet is appropriate for general high school biology students, and the “Version 2” worksheet is appropriate for AP/IB Biology and undergraduate students. 

The “Resource Google Folder” link directs to a Google Drive folder of resource documents in the Google Docs format. Not all downloadable documents for the resource may be available in this format. The Google Drive folder is set as “View Only”; to save a copy of a document in this folder to your Google Drive, open that document, then select File → “Make a copy.” These documents can be copied, modified, and distributed online following the Terms of Use listed in the “Details” section below, including crediting BioInteractive.

An audio descriptive version of the animation is available via our media player by clicking the "AD" button in the lower left hand corner of the media player.

Student Learning Targets

• Identify structural components of SARS-CoV-2.
• Describe the steps in the SARS-CoV-2 replication cycle. 
• Explain how mutations arise in a viral genome.
• Describe how a virus can change over time due to mutations.
• Outline different ways to detect a viral infection.
• Describe how different types of vaccines expose the immune system to specific antigens.
• Explain how antigens stimulate a natural immune response, including the concepts of antibodies and immune memory.  

Estimated Time

adenovirus, antibody, antigen, B cell, COVID-19, coronavirus, envelope, mRNA, mutation, replication, RT-PCR, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), spike protein

Primary Literature

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Lessons Learned from the Launch and Implementation of the COVID-19 Contact Tracing Program in New York City: a Qualitative Study

• Original Article
• Published: 29 August 2024

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• Margaret M. Paul   ORCID: orcid.org/0000-0003-3281-6234 1 ,
• Lorraine Kwok 2 ,
• Rachel E. Massar 2 ,
• Michelle Chau 2 ,
• Rita Larson 2 ,
• Stefanie Bendik 2 ,
• Lorna E. Thorpe 2 ,
• Anna Bershteyn 2 ,
• Nadia Islam 2 &
• Carolyn A. Berry 2  

On June 1, 2020, NYC Health + Hospitals, in partnership with the NYC Department of Health and Mental Hygiene, other city agencies, and a large network of community partners, launched the New York City Test & Trace (T2) COVID-19 response program to identify and isolate cases, reduce transmission through contact tracing, and provide support to residents during isolation or quarantine periods. In this paper, we describe lessons learned with respect to planning and implementation of case notification and contact tracing. Our findings are based on extensive document review and analysis of 74 key informant interviews with T2 leadership and frontline staff, cases, and contacts conducted between January and September 2022. Interviews elicited respondent background, history of program development, program leadership and structure, goals of the program, program evolution, staffing, data systems, elements of community engagement, trust with community, program reach, timeliness, equity, general barriers and challenges, general facilitators and best practices, and recommendations/improvement for the program. Facilitators and barriers revealed in the interviews primarily revolved around hiring and managing staff, data and technology, and quality of interactions with the public. Based on these facilitators and barriers, we identify suggestions to support effective planning and response for future case notification and contact tracing programs, including recommendations for planning during latent periods, case management and data systems, and processes for outreach to cases and contacts.

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Acknowledgements

This work was supported by NYC Health + Hospitals (1007645); L.T). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA

Margaret M. Paul

Department of Population Health, NYU Grossman School of Medicine, 180 Madison Avenue, New York, NY, 10016, USA

Lorraine Kwok, Rachel E. Massar, Michelle Chau, Rita Larson, Stefanie Bendik, Lorna E. Thorpe, Anna Bershteyn, Nadia Islam & Carolyn A. Berry

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Paul, M.M., Kwok, L., Massar, R.E. et al. Lessons Learned from the Launch and Implementation of the COVID-19 Contact Tracing Program in New York City: a Qualitative Study. J Urban Health (2024). https://doi.org/10.1007/s11524-024-00898-0

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Accepted : 09 July 2024

Published : 29 August 2024

DOI : https://doi.org/10.1007/s11524-024-00898-0

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