research papers in virology

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Virology articles from across Nature Portfolio

Virology is the scientific discipline concerned with the study of the biology of viruses and viral diseases, including the distribution, biochemistry, physiology, molecular biology, ecology, evolution and clinical aspects of viruses.

Aged nasal epithelium is more prone to severe COVID-19

Age is the single greatest risk factor driving mortality after encounter with SARS-CoV-2. A new study shows that the composition of nasal epithelial cells varies across ages, facilitating SARS-CoV-2 growth and spread in older people.

• Ivan Zanoni

Blocking cell death limits lung damage and inflammation from influenza

Animals that receive an inhibitor of an antiviral cell-death response called necroptosis are less likely to die of influenza even at a late stage of infection. This has implications for the development of therapies for respiratory diseases.

• Nishma Gupta

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Latest Research and Reviews

Concomitant human papillomavirus (HPV) vaccination and screening for elimination of HPV and cervical cancer

Here the authors report baseline results of a population-based trial testing concomitant human papillomavirus (HPV) vaccination and HPV-based screening of young women in Sweden and, using a transmission model, suggest that this approach may reduce high-risk HPV infections.

• Laila Sara Arroyo Mühr
• Andrea Gini
• Joakim Dillner

Dynamic diversity of SARS-CoV-2 genetic mutations in a lung transplantation patient with persistent COVID-19

In this study, the authors report the case of a patient who underwent lung transplantation and subsequently developed COVID-19 that resulted in persistent infection. Following antiviral treatment, SARS-CoV-2 (BA.5) showed dynamic genetic diversity with remdesivir resistant mutations leading to enhanced fusogenicity.

• Hidetoshi Igari
• Seiichiro Sakao

CD8 + T-cell responses towards conserved influenza B virus epitopes across anatomical sites and age

Influenza B viruses are linked to significant morbidity and mortality, and yet their immunobiology is comparatively poorly understood. Here Menon et al identify influenza B virus-specific CD8 + T cell epitopes and characterise these in adults, children and the elderly.

• Tejas Menon
• Patricia T. Illing
• Katherine Kedzierska

HIV transmission dynamics and population-wide drug resistance in rural South Africa

There is limited data on drug resistance in South African communities strongly affected by HIV. In this study, the authors observed low levels of resistance to newer drugs but widespread resistance to older HIV medications in a South African community. Resistance to rilpivirine was detected even in untreated individuals.

• Steven A. Kemp
• Kimia Kamelian
• Ravindra K. Gupta

Changing epidemiology of parvovirus B19 in the Netherlands since 1990, including its re-emergence after the COVID-19 pandemic

• Anne Russcher
• Michiel van Boven
• Aloys C. M. Kroes

Oxygen enhances antiviral innate immunity through maintenance of EGLN1-catalyzed proline hydroxylation of IRF3

Oxygen is an essential requirement for aerobic organisms. Here the authors explore the role of oxygen in the antiviral innate response in multiple models of infection and suggest oxygen enhances the antiviral innate response via EGLN1 hydroxylation of IRF3.

• Jinhua Tang

News and Comment

Chinese virologist who was first to share COVID genome sleeps on street after lab shuts

Zhang Yongzhen shared the genomic sequence of SARS-CoV-2 with the world, speeding the development of vaccines.

• Smriti Mallapaty

Scientists tried to give people COVID — and failed

Researchers deliberately infect participants with SARS-CoV-2 in ‘challenge’ trials — but high levels of immunity complicate efforts to test vaccines and treatments.

• Ewen Callaway

Bird flu virus has been spreading among US cows for months, RNA reveals

Genomic analysis suggests that the outbreak probably began in December or January, but a shortage of data is hampering efforts to pin down the source.

Bird flu in US cows: is the milk supply safe?

Pasteurized milk is probably not a threat to people, but fresh milk droplets on milking equipment could be spreading the virus in a herd.

• Julian Nowogrodzki

The complex life of the HIV-1 full-length RNA

In this Journal Club, Ricardo Soto-Rifo discusses a study on intron-containing HIV-1 RNA, revealing its role as a pathogen-associated molecular pattern in myeloid cells, which has implications for immune activation, inflammation and clinical outcomes.

• Ricardo Soto-Rifo

WHO redefines airborne transmission: what does that mean for future pandemics?

The World Health Organization was criticized for being too slow to classify COVID-19 as airborne. Will the new terminology help next time?

• Bianca Nogrady

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• Virology, transmission...

Virology, transmission, and pathogenesis of SARS-CoV-2

Read our latest coverage of the coronavirus outbreak.

• Related content
• Peer review
• Muge Cevik , clinical lecturer 1 2 ,
• Krutika Kuppalli , assistant professor 3 ,
• Jason Kindrachuk , assistant professor of virology 4 ,
• Malik Peiris , professor of virology 5
• 1 Division of Infection and Global Health Research, School of Medicine, University of St Andrews, St Andrews, UK
• 2 Specialist Virology Laboratory, Royal Infirmary of Edinburgh, Edinburgh, UK and Regional Infectious Diseases Unit, Western General Hospital, Edinburgh, UK
• 3 Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC, USA
• 4 Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada
• 5 School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
• Correspondence to M Cevik mc349{at}st-andrews.ac.uk

What you need to know

SARS-CoV-2 is genetically similar to SARS-CoV-1, but characteristics of SARS-CoV-2—eg, structural differences in its surface proteins and viral load kinetics—may help explain its enhanced rate of transmission

In the respiratory tract, peak SARS-CoV-2 load is observed at the time of symptom onset or in the first week of illness, with subsequent decline thereafter, indicating the highest infectiousness potential just before or within the first five days of symptom onset

Reverse transcription polymerase chain reaction (RT-PCR) tests can detect viral SARS-CoV-2 RNA in the upper respiratory tract for a mean of 17 days; however, detection of viral RNA does not necessarily equate to infectiousness, and viral culture from PCR positive upper respiratory tract samples has been rarely positive beyond nine days of illness

Symptomatic and pre-symptomatic transmission (1-2 days before symptom onset), is likely to play a greater role in the spread of SARS-CoV-2 than asymptomatic transmission

A wide range of virus-neutralising antibodies have been reported, and emerging evidence suggests that these may correlate with severity of illness but wane over time

Since the emergence of SARS-CoV-2 in December 2019, there has been an unparalleled global effort to characterise the virus and the clinical course of disease. Coronavirus disease 2019 (covid-19), caused by SARS-CoV-2, follows a biphasic pattern of illness that likely results from the combination of an early viral response phase and an inflammatory second phase. Most clinical presentations are mild, and the typical pattern of covid-19 more resembles an influenza-like illness—which includes fever, cough, malaise, myalgia, headache, and taste and smell disturbance—rather than severe pneumonia (although emerging evidence about long term consequences is yet to be understood in detail). 1 In this review, we provide a broad update on the emerging understanding of SARS-CoV-2 pathophysiology, including virology, transmission dynamics, and the immune response to the virus. Any of the mechanisms and assumptions discussed in the article and in our understanding of covid-19 may be revised as further evidence emerges.

What we know about the virus

SARS-CoV-2 is an enveloped β-coronavirus, with a genetic sequence very similar to SARS-CoV-1 (80%) and bat coronavirus RaTG13 (96.2%). 2 The viral envelope is coated by spike (S) glycoprotein, envelope (E), and membrane (M) proteins ( fig 1 ). Host cell binding and entry are mediated by the S protein. The first step in infection is virus binding to a host cell through its target receptor. The S1 sub-unit of the S protein contains the receptor binding domain that binds to the peptidase domain of angiotensin-converting enzyme 2 (ACE 2). In SARS-CoV-2 the S2 sub-unit is highly preserved and is considered a potential antiviral target. The virus structure and replication cycle are described in figure 1 .

(1) The virus binds to ACE 2 as the host target cell receptor in synergy with the host’s transmembrane serine protease 2 (cell surface protein), which is principally expressed in the airway epithelial cells and vascular endothelial cells. This leads to membrane fusion and releases the viral genome into the host cytoplasm (2). Stages (3-7) show the remaining steps of viral replication, leading to viral assembly, maturation, and virus release

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Coronaviruses have the capacity for proofreading during replication, and therefore mutation rates are lower than in other RNA viruses. As SARS-CoV-2 has spread globally it has, like other viruses, accumulated some mutations in the viral genome, which contains geographic signatures. Researchers have examined these mutations to study virus characterisation and understand epidemiology and transmission patterns. In general, the mutations have not been attributed to phenotypic changes affecting viral transmissibility or pathogenicity. The G614 variant in the S protein has been postulated to increase infectivity and transmissibility of the virus. 3 Higher viral loads were reported in clinical samples with virus containing G614 than previously circulating variant D614, although no association was made with severity of illness as measured by hospitalisation outcomes. 3 These findings have yet to be confirmed with regards to natural infection.

Why is SARS-CoV-2 more infectious than SARS-CoV-1?

SARS-CoV-2 has a higher reproductive number (R 0 ) than SARS-CoV-1, indicating much more efficient spread. 1 Several characteristics of SARS-CoV-2 may help explain this enhanced transmission. While both SARS-CoV-1 and SARS-CoV-2 preferentially interact with the angiotensin-converting enzyme 2 (ACE 2) receptor, SARS-CoV-2 has structural differences in its surface proteins that enable stronger binding to the ACE 2 receptor 4 and greater efficiency at invading host cells. 1 SARS-CoV-2 also has greater affinity (or bonding) for the upper respiratory tract and conjunctiva, 5 thus can infect the upper respiratory tract and can conduct airways more easily. 6

Viral load dynamics and duration of infectiousness

Viral load kinetics could also explain some of the differences between SARS-CoV-2 and SARS-CoV-1. In the respiratory tract, peak SARS-CoV-2 load is observed at the time of symptom onset or in the first week of illness, with subsequent decline thereafter, which indicates the highest infectiousness potential just before or within the first five days of symptom onset ( fig 2 ). 7 In contrast, in SARS-CoV-1 the highest viral loads were detected in the upper respiratory tract in the second week of illness, which explains its minimal contagiousness in the first week after symptom onset, enabling early case detection in the community. 7

After the initial exposure, patients typically develop symptoms within 5-6 days (incubation period). SARS-CoV-2 generates a diverse range of clinical manifestations, ranging from mild infection to severe disease accompanied by high mortality. In patients with mild infection, initial host immune response is capable of controlling the infection. In severe disease, excessive immune response leads to organ damage, intensive care admission, or death. The viral load peaks in the first week of infection, declines thereafter gradually, while the antibody response gradually increases and is often detectable by day 14 (figure adapted with permission from https://www.sciencedirect.com/science/article/pii/S009286742030475X ; https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30230-7/fulltext )

Quantitative reverse transcription polymerase chain reaction (qRT-PCR) technology can detect viral SARS-CoV-2 RNA in the upper respiratory tract for a mean of 17 days (maximum 83 days) after symptom onset. 7 However, detection of viral RNA by qRT-PCR does not necessarily equate to infectiousness, and viral culture from PCR positive upper respiratory tract samples has been rarely positive beyond nine days of illness. 5 This corresponds to what is known about transmission based on contact tracing studies, which is that transmission capacity is maximal in the first week of illness, and that transmission after this period has not been documented. 8 Severely ill or immune-compromised patients may have relatively prolonged virus shedding, and some patients may have intermittent RNA shedding; however, low level results close to the detection limit may not constitute infectious viral particles. While asymptomatic individuals (those with no symptoms throughout the infection) can transmit the infection, their relative degree of infectiousness seems to be limited. 9 10 11 People with mild symptoms (paucisymptomatic) and those whose symptom have not yet appeared still carry large amounts of virus in the upper respiratory tract, which might contribute to the easy and rapid spread of SARS-CoV-2. 7 Symptomatic and pre-symptomatic transmission (one to two days before symptom onset) is likely to play a greater role in the spread of SARS-CoV-2. 10 12 A combination of preventive measures, such as physical distancing and testing, tracing, and self-isolation, continue to be needed.

Route of transmission and transmission dynamics

Like other coronaviruses, the primary mechanism of transmission of SARS-CoV-2 is via infected respiratory droplets, with viral infection occurring by direct or indirect contact with nasal, conjunctival, or oral mucosa, when respiratory particles are inhaled or deposited on these mucous membranes. 6 Target host receptors are found mainly in the human respiratory tract epithelium, including the oropharynx and upper airway. The conjunctiva and gastrointestinal tracts are also susceptible to infection and may serve as transmission portals. 6

Transmission risk depends on factors such as contact pattern, environment, infectiousness of the host, and socioeconomic factors, as described elsewhere. 12 Most transmission occurs through close range contact (such as 15 minutes face to face and within 2 m), 13 and spread is especially efficient within households and through gatherings of family and friends. 12 Household secondary attack rates (the proportion of susceptible individuals who become infected within a group of susceptible contacts with a primary case) ranges from 4% to 35%. 12 Sleeping in the same room as, or being a spouse of an infected individual increases the risk of infection, but isolation of the infected person away from the family is related to lower risk of infection. 12 Other activities identified as high risk include dining in close proximity with the infected person, sharing food, and taking part in group activities 12 The risk of infection substantially increases in enclosed environments compared with outdoor settings. 12 For example, a systematic review of transmission clusters found that most superspreading events occurred indoors. 11 Aerosol transmission can still factor during prolonged stay in crowded, poorly ventilated indoor settings (meaning transmission could occur at a distance >2 m). 12 14 15 16 17

The role of faecal shedding in SARS-CoV-2 transmission and the extent of fomite (through inanimate surfaces) transmission also remain to be fully understood. Both SARS-CoV-2 and SARS-CoV-1 remain viable for many days on smooth surfaces (stainless steel, plastic, glass) and at lower temperature and humidity (eg, air conditioned environments). 18 19 Thus, transferring infection from contaminated surfaces to the mucosa of eyes, nose, and mouth via unwashed hands is a possible route of transmission. This route of transmission may contribute especially in facilities with communal areas, with increased likelihood of environmental contamination. However, both SARS-CoV-1 and SARS-CoV-2 are readily inactivated by commonly used disinfectants, emphasising the potential value of surface cleaning and handwashing. SARS-CoV-2 RNA has been found in stool samples and RNA shedding often persists for longer than in respiratory samples 7 ; however, virus isolation has rarely been successful from the stool. 5 7 No published reports describe faecal-oral transmission. In SARS-CoV-1, faecal-oral transmission was not considered to occur in most circumstances; but, one explosive outbreak was attributed to aerosolisation and spread of the virus across an apartment block via a faulty sewage system. 20 It remains to be seen if similar transmission may occur with SARS-CoV-2.

Pathogenesis

Viral entry and interaction with target cells.

SARS-CoV-2 binds to ACE 2, the host target cell receptor. 1 Active replication and release of the virus in the lung cells lead to non-specific symptoms such as fever, myalgia, headache, and respiratory symptoms. 1 In an experimental hamster model, the virus causes transient damage to the cells in the olfactory epithelium, leading to olfactory dysfunction, which may explain temporary loss of taste and smell commonly seen in covid-19. 21 The distribution of ACE 2 receptors in different tissues may explain the sites of infection and patient symptoms. For example, the ACE 2 receptor is found on the epithelium of other organs such as the intestine and endothelial cells in the kidney and blood vessels, which may explain gastrointestinal symptoms and cardiovascular complications. 22 Lymphocytic endotheliitis has been observed in postmortem pathology examination of the lung, heart, kidney, and liver as well as liver cell necrosis and myocardial infarction in patients who died of covid-19. 1 23 These findings indicate that the virus directly affects many organs, as was seen in SARS-CoV-1 and influenzae.

Much remains unknown. Are the pathological changes in the respiratory tract or endothelial dysfunction the result of direct viral infection, cytokine dysregulation, coagulopathy, or are they multifactorial? And does direct viral invasion or coagulopathy directly contribute to some of the ischaemic complications such as ischaemic infarcts? These and more, will require further work to elucidate.

Immune response and disease spectrum ( figure 2 )

After viral entry, the initial inflammatory response attracts virus-specific T cells to the site of infection, where the infected cells are eliminated before the virus spreads, leading to recovery in most people. 24 In patients who develop severe disease, SARS-CoV-2 elicits an aberrant host immune response. 24 25 For example, postmortem histology of lung tissues of patients who died of covid-19 have confirmed the inflammatory nature of the injury, with features of bilateral diffuse alveolar damage, hyaline-membrane formation, interstitial mononuclear inflammatory infiltrates, and desquamation consistent with acute respiratory distress syndrome (ARDS), and is similar to the lung pathology seen in severe Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). 26 27 A distinctive feature of covid-19 is the presence of mucus plugs with fibrinous exudate in the respiratory tract, which may explain the severity of covid-19 even in young adults. 28 This is potentially caused by the overproduction of pro-inflammatory cytokines that accumulate in the lungs, eventually damaging the lung parenchyma. 24

Some patients also experience septic shock and multi-organ dysfunction. 24 For example, the cardiovascular system is often involved early in covid-19 disease and is reflected in the release of highly sensitive troponin and natriuretic peptides. 29 Consistent with the clinical context of coagulopathy, focal intra-alveolar haemorrhage and presence of platelet-fibrin thrombi in small arterial vessels is also seen. 27 Cytokines normally mediate and regulate immunity, inflammation, and haematopoiesis; however, further exacerbation of immune reaction and accumulation of cytokines in other organs in some patients may cause extensive tissue damage, or a cytokine release syndrome (cytokine storm), resulting in capillary leak, thrombus formation, and organ dysfunction. 24 30

Mechanisms underlying the diverse clinical outcomes

Clinical outcomes are influenced by host factors such as older age, male sex, and underlying medical conditions, 1 as well as factors related to the virus (such as viral load kinetics), host-immune response, and potential cross-reactive immune memory from previous exposure to seasonal coronaviruses ( box 1 ).

Risk factors associated with the development of severe disease, admission to intensive care unit, and mortality

Underlying condition.

Hypertension

Cardiovascular disease

Chronic obstructive pulmonary disease

Presentation

Higher fever (≥39°C on admission)

Dyspnoea on admission

Higher qSOFA score

Laboratory markers

Neutrophilia/lymphopenia

Raised lactate and lactate dehydrogenase

Raised C reactive protein

Raised ferritin

Raised IL-6

Raised ACE2

D-dimer >1 μg/mL

Sex-related differences in immune response have been reported, revealing that men had higher plasma innate immune cytokines and chemokines at baseline than women. 31 In contrast, women had notably more robust T cell activation than men, and among male participants T cell activation declined with age, which was sustained among female patients. These findings suggest that adaptive immune response may be important in defining the clinical outcome as older age and male sex is associated with increased risk of severe disease and mortality.

Increased levels of pro-inflammatory cytokines correlate with severe pneumonia and increased ground glass opacities within the lungs. 30 32 In people with severe illness, increased plasma concentrations of inflammatory cytokines and biomarkers were observed compared with people with non-severe illness. 30 33 34

Emerging evidence suggests a correlation between viral dynamics, the severity of illness, and disease outcome. 7 Longitudinal characteristics of immune response show a correlation between the severity of illness, viral load, and IFN- α, IFN-γ, and TNF-α response. 34 In the same study many interferons, cytokines, and chemokines were elevated early in disease for patients who had severe disease and higher viral loads. This emphasises that viral load may drive these cytokines and the possible pathological roles associated with the host defence factors. This is in keeping with the pathogenesis of influenza, SARS, and MERS whereby prolonged viral shedding was also associated with severity of illness. 7 35

Given the substantial role of the immune response in determining clinical outcomes, several immunosuppressive therapies aimed at limiting immune-mediated damage are currently in various phases of development ( table 1 ).

Therapeutics currently under investigation

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Immune response to the virus and its role in protection

Covid-19 leads to an antibody response to a range of viral proteins, but the spike (S) protein and nucleocapsid are those most often used in serological diagnosis. Few antibodies are detectable in the first four days of illness, but patients progressively develop them, with most achieving a detectable response after four weeks. 36 A wide range of virus-neutralising antibodies have been reported, and emerging evidence suggests that these may correlate with severity but wane over time. 37 The duration and protectivity of antibody and T cell responses remain to be defined through studies with longer follow-up. CD-4 T cell responses to endemic human coronaviruses appear to manifest cross-reactivity with SARS-CoV-2, but their role in protection remains unclear. 38

Unanswered questions

Further understanding of the pathogenesis for SARS-CoV-2 will be vital in developing therapeutics, vaccines, and supportive care modalities in the treatment of covid-19. More data are needed to understand the determinants of healthy versus dysfunctional response and immune markers for protection and the severity of disease. Neutralising antibodies are potential correlates of protection, but other protective antibody mechanisms may exist. Similarly, the protective role of T cell immunity and duration of both antibody and T cell responses and the correlates of protection need to be defined. In addition, we need optimal testing systems and technologies to support and inform early detection and clinical management of infection. Greater understanding is needed regarding the long term consequences following acute illness and multisystem inflammatory disease, especially in children.

Education into practice

How would you describe SARS-CoV-2 transmission routes and ways to prevent infection?

How would you describe to a patient why cough, anosmia, and fever occur in covid-19?

Questions for future research

What is the role of the cytokine storm and how could it inform the development of therapeutics, vaccines, and supportive care modalities?

What is the window period when patients are most infectious?

Why do some patients develop severe disease while others, especially children, remain mildly symptomatic or do not develop symptoms?

What are the determinants of healthy versus dysfunctional response, and the biomarkers to define immune correlates of protection and disease severity for the effective triage of patients?

What is the protective role of T cell immunity and duration of both antibody and T cell responses, and how would you define the correlates of protection?

How patients were involved in the creation of this article

No patients were directly involved in the creation of this article.

How this article was created

We searched PubMed from 2000 to 18 September 2020, limited to publications in English. Our search strategy used a combination of key words including “COVID-19,” “SARS-CoV-2,” “SARS”, “MERS,” “Coronavirus,” “Novel Coronavirus,” “Pathogenesis,” “Transmission,” “Cytokine Release,” “immune response,” “antibody response.” These sources were supplemented with systematic reviews. We also reviewed technical documents produced by the Centers for Disease Control and Prevention and World Health Organization technical documents.

Author contributions: MC, KK, JK, MP drafted the first and subsequent versions of the manuscript and all authors provided critical feedback and contributed to the manuscript.

Competing interests The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none.

Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests

Provenance and peer review: commissioned; externally peer reviewed.

This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

• Bamford CGG ,
• Fischer WM ,
• Gnanakaran S ,
• Sheffield COVID-19 Genomics Group
• Corbett KS ,
• Corman VM ,
• Guggemos W ,
• Cheung MC ,
• Perera RAPM ,
• Cheng H-Y ,
• Taiwan COVID-19 Outbreak Investigation Team
• Meyerowitz E ,
• Richterman A ,
• Nergiz AI ,
• Maraolo AE ,
• Buitrago-Garcia D ,
• Egli-Gany D ,
• Counotte MJ ,
• ↵ European Centre for Disease Prevention and Control. Surveillance definitions for COVID-19. 2020. https://www.ecdc.europa.eu/en/covid-19/surveillance/surveillance-definitions .
• Klompas M ,
• ↵ Centers for Disease Control and Prevention. How COVID-19 spreads. 2020. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/how-covid-spreads.html
• ↵ Centers for Disease Control and Prevention. Scientific brief: SARS-CoV-2 and potential airborne transmission. 2020. https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-sars-cov-2.html
• Perera MRA ,
• van Doremalen N ,
• Bushmaker T ,
• Morris DH ,
• Monteil V ,
• Flammer AJ ,
• Steiger P ,
• Mangalmurti N ,
• Blanco-Melo D ,
• Nilsson-Payant BE ,
• Carsana L ,
• Sonzogni A ,
• ↵ Takahashi T, Ellingson MK, Wong P, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature 2020. https://pubmed.ncbi.nlm.nih.gov/32846427/
• Yale IMPACT Team
• CAP-China Network
• Perera RA ,
• Merrick B ,
• Grifoni A ,
• Weiskopf D ,
• Ramirez SI ,

• Open access
• Published: 29 July 2020

SARS-CoV-2: characteristics and current advances in research

• Yicheng Yang 1 , 2 ,
• Zhiqiang Xiao 3 ,
• Kaiyan Ye 4 ,
• Xiaoen He 2 ,
• Zhiran Qin 2 ,
• Jianghai Yu 2 ,
• Jinxiu Yao 5 ,
• Qinghua Wu 2 ,
• Zhang Bao 2 &
• Wei Zhao 2  

Virology Journal volume  17 , Article number:  117 ( 2020 ) Cite this article

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Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has spread rapidly across the world and become an international public health emergency. Both SARS-CoV-2 and SARS-CoV belong to subfamily Coronavirinae in the family Coronaviridae of the order Nidovirales and they are classified as the SARS-like species while belong to different cluster. Besides, viral structure, epidemiology characteristics and pathological characteristics are also different. We present a comprehensive survey of the latest coronavirus—SARS-CoV-2—from investigating its origin and evolution alongside SARS-CoV. Meanwhile, pathogenesis, cardiovascular disease in COVID-19 patients, myocardial injury and venous thromboembolism induced by SARS-CoV-2 as well as the treatment methods are summarized in this review.

The COVID-19 pandemic has resulted in more than 6.6 million confirmed cases worldwide. Previous studies showed that both SARS-CoV-2 and SARS-CoV belong to the subfamily Coronavirinae of the Nidovirales coronaviridae , and are classified as SARS-like species, but belong to different clusters. To further explore the characteristics of SARS-CoV-2, we compared different aspects of the virus with those of SARS-CoV; the clinical manifestations and treatment methods are also summarized.

Introduction

Coronaviruses belong to the subfamily Coronavirinae in the family Coronaviridae of the order Nidovirales and can cause respiratory, digestive, and nervous system diseases in humans and many other animals. Coronavirus particles are spherical with a diameter of approximately 80 to 160 mm. The envelope surface is covered with spike (S) protein, and the membrane (M) proteins and envelope (E) proteins are located among the S proteins. The genomic RNA and phosphorylated nucleocapsid (N) protein form a spiral nucleocapsid, which is located within the envelope [ 1 , 2 ]. The coronavirus genome is comprised of a single-stranded positive-strand RNA ranging from 26 Kb to 32 Kb in length, constituting the longest known genome among RNA viruses [ 3 ]. This genome has a 5′ cap structure, a 3′ polyadenylate tail structure, and six open reading frames (ORFs), of which the first (ORF1) near the 5′ terminus encodes 16 non-structural proteins (nsp1–16) involved in viral replication and transcription; other ORFs encode the four major structural proteins (S, M, N, and P) and eight accessory proteins (3a, 3b, p6, 7a, 7b, 8b, 9b, and ORF14), playing an important role in the assembly of viral particles.

According to genetic and antigenic characteristics, coronaviruses can be divided into four genera: α, β, γ, and δ. Among them, α and β coronaviruses only infect mammals, while γ and δ mainly infect birds, although some can also infect mammals [ 4 , 5 ]. Except for SARS-CoV and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), most coronaviruses do not cause severe diseases in humans. It has been confirmed that the recent outbreak and epidemic of coronavirus disease 2019 (COVID-19) was caused by a new coronavirus that has been named SARS-CoV-2. Different from SARS-CoV and MERS-CoV in genetics and epidemiology, SARS-CoV-2 is a novel β-coronavirus [ 6 , 7 ]. As of now, three types of highly pathogenic coronaviruses have been confirmed, namely SARS-CoV, MERS-CoV, and SARS-CoV-2 [ 8 ].

In our review, we explore the differences in the origin and evolution, amino acid composition and protein structure, epidemiological and pathological characteristics between SARS-CoV-2 and SARS-CoV. In addition, the pathogenesis of SARS-CoV-2 has been summarized. Based on our expertise, comorbidity of cardiovascular diseases (CVD) in COVID-19 patients and SARS-CoV-2-induced myocardial injury and venous thromboembolism (VTE) are fully discussed, and medicines with recent clinical trial outcomes are also introduced.

Differences between SARS-CoV-2 and SARS-CoV

Classification.

According to the principle of international commission on virus classification, the coronavirus identification mainly depends on the similarity of the amino acid sequences of the seven domains encoded by ORF1ab, including ADRP, nsp5, and nsp12–16. Due to the extremely similar (more than 90%) amino acid sequences in the seven domains, both SARS-CoV-2 and SARS-CoV belong to the subfamily Coronavirinae in the family Coronaviridae of the order Nidovirales and are classified as SARS-like species, although they are classified into different clusters. The former belongs to the bat-like coronavirus cluster and the latter to the SARS cluster. Phylogenetic analysis showed that SARS-CoV-2 has a longer branch length compared to its closest relatives, including bat-SL-CoVZC45 and bat-SL-CoVZXC21; furthermore, it is genetically different from SARS-CoV. SARS-CoV-2 has only 79.5 and 40% homology with SARS-CoV and MERS-CoV, respectively, indicating a large genetic distance. At the same time, the S-protein homology between SARS-CoV and SARS-CoV-2 is also relatively low at 76.5% [ 9 , 10 , 11 , 12 ].

Amino acid composition and protein structure

While SARS-CoV-2 is very similar to SARS-CoV in amino acid composition and protein structure, with both having an Orf1ab encoding 16 predicted Nsps as well as the 4 typical coronavirus structural proteins, they also show some differences, mainly in the S, ORF8, ORF3b, and ORF10 proteins, with limited detectable homology between them.

Like SARS-CoV, the entry of SARS-CoV-2 is mediated by the recognition of the receptor binding domain (RBD) in the S protein and the angiotensin converting enzyme 2 (ACE2) receptor on the surface of the host cell, and the activation of S protein is related to TMPRSS2, whose inhibitors can prevent virus invasion [ 13 ]. Most of the SARS-CoV-induced polyclonal antibodies can prevent the S-mediated entry of the virus, which further illustrates the similarity between these two coronaviruses. However, according to previous researches, the outer subdomain of the receptor-binding domain in the S protein of SARS-CoV-2 has only 40% amino acid homology with other SARS-associated coronaviruses [ 3 ]. A recent research found that Furin protease cleavage site exists at the boundary between the S1 subunit and S2 subunit in the S protein of SARS-CoV-2, and it is processed during the biosynthesis [ 14 ]. This is similar to several highly pathogenic avian influenza viruses [ 15 ] and pathogenic Newcastle disease virus [ 16 ], but distinguishes SARS-CoV-2 from SARS-CoV. The existence of the cleavage site of the Furin protease enhances the tissue and cell tropism and transmissibility of SARS-CoV-2, and alters its pathogenicity. Wrapp et al. [ 17 ] obtained the trimeric structure of the S protein by 3D reconstruction technology based on the genomic sequence of SARS-CoV-2, and found that it is structurally different from that of SARS-CoV. In addition, the affinity of S protein of SARS-CoV-2 to ACE2 increased by 10–20 times compared with that of SARS-CoV. Blocking the process of viral entry is an important way to prevent and control viral infections; identifying and understanding the protein molecules on the surface of the new coronavirus, related receptors of target cell, as well as their interaction mechanisms can provide a basis for effectively preventing viruses from invading host cells. RBD is recognized primarily via polar residues by the extracellular peptidase domain of ACE2. Yan et al. [ 18 ] analyzed the electron microscope structure of the complex of S protein and ACE2, and found that in the procedure of the virus-target cell binding, the loop region on RBD crossed the α1 helix of ACE2, and the loop regions of β3, β4 and α2 helix are also involved in the combination of RBD and ACE2. Superimposing of the structures of SARS-COV-RBD and SARS-COV-2-RBD suggests a very high degree of similarity between the two, but there are still differences. The R426, Y484, T487, V404, and L472 residues in SARS-COV-RBD were replaced by N439, Q498, N501, K417, and F486 in the SARS-COV-2-RBD respectively. The replacement of L472 by F486 will enhance the van der Waals effect, and that of R426 by N439 will eliminate the salt bridge effect of D329 in ACE2, which, however, would be strengthened when V404 is replaced by K417. The existence of these mutations may be a significant reason SARS-COV-specific RBD antibody drugs fail to work on SARS-COV-2.

The motif VLVVL (amino acids 75–79) was reported in SARS-CoV ORF8b, which can trigger the intracellular stress pathway and activate the NLRP3 endosome, while no functional domains containing this motif has been found in SARS-CoV-2. ORF8 is related to the evolution of SARS-associated coronaviruses, and plays a significant role in virus replication, transmission, and adaptation to its hosts. In SARS-CoV-2, ORF8 consists of 121 amino acids, while it exists as ORF8a (39 amino acids) and ORF8b (84 amino acids) in SARS-CoV. The ORF3b protein contains 154 amino acids in SARS-CoV, but only 67 amino acids in SARS-CoV-2. In addition, the ORF3b protein of SARS-CoV-2 contains four new helical structures, and shows no homology to that of SARS-CoV. Although ORF3b protein is not necessary for virus replication, it may be related to its pathogenicity and its importance in SARS-CoV-2 requires further study [ 19 ].

Recently, a study carried out by multiple teams in the United States, France, and the UK cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells, and suggested that ORF10 of SARS-CoV-2 shows limited homology with that of SARS-CoV. The study found that ORF10 of SARS-CoV-2 is small in size (38 amino acids), but contains an alpha helical region, which can be linked to a Cullin 2 (CUL2) RING E3 ligase complex, especially the CUL2ZYG11B complex, and hijack it for ubiquitination and restriction factor degradation. Alternatively, ZYG11B may bind to the N-terminal glycine in Orf10 to target it for degradation, which is closely related to virus replication [ 20 ].

Currently, it is believed that the SARS-CoV-2 genome is more stable than SARS-CoV, but it is still necessary to strengthen the monitoring of viral genome mutations as the epidemic progresses. Some large-scale viral genome studies suggest that 149 mutation sites have appeared in SARS-CoV-2. Due to the sequence difference in site 28,144 in the viral RNA genome, SARS-CoV-2 is divided into two subtypes: L and S. The L type spreads more widely, and has more mutations and a stronger ability to spread. Compared with other coronavirus, the gene sequence of S protein in SARS-CoV-2 changes greatly, suggesting that this segment may show a higher mutation rate [ 21 ]. Su et al. used a second-generation sequencing platform to analyze the nasal swab samples of patients diagnosed with COVID-19 and found that the 3′-end of the SARS-CoV-2 genome has a fragment with 382 nt missing, resulting in the destruction of the function of the ORF8 region, which may relate to how SARS-CoV-2 adapts to human survival [ 22 ]. Distinctions in the structure between SARS-CoV and SARS-CoV-2 are shown in Fig.  1 .

Distinctions of amino acid composition and protein structure. Differences between SARS-CoV and SARS-CoV-2 are mainly in S protein, ORF8 protein and ORF3b protien. a The external subdomain of the receptor binding domain of the spike protein in SARS-CoV-2 shares only 40% amino acid identity with other SARS-related coronaviruses; b ORF8 in SARS-CoV-2 does not contain a known functional domain or motif while in SARS-CoV ORF8b the presence of the aggregation motif VLVVL has been found; c The ORF8a protein is absent in SARS-CoV-2; There are 121 amino acids that encode the 8b protein in SARS-CoV-2, while only 84 are involved in SARS-CoV. d ORF3b of SARS-CoV-2 has a novel protein with four helices and 67 amino acids that encode the 3b protein in SARS-CoV-2 while 154 amino acids are involved in SARS-CoV

Epidemiological characteristics

Studies indicate that SARS-CoV has an incubation period of 2 to 10 days and a median incubation period of 4 to 7 days, while the incubation period of SARS-CoV-2 is mostly within 14 days, and the median is 3–4 days.

Sources of infection

The SARS epidemic in 2003 first occurred in Guangdong Province. Sources of SARS-CoV infection include infected animals and humans. At present, it is generally believed that the virus originates from bats, and civet is a possible intermediate host, and humans are the final hosts [ 23 ].

At the end of 2019, the first outbreak of pneumonia caused by SARS-CoV-2 occurred in Wuhan, Hubei [ 24 ]. Besides infected animals and COVID-19 patients, asymptomatic infectors are the most important source of infection for SARS-CoV-2 [ 25 ]. Studies have demonstrated that SARS-CoV-2 is of bat origin [ 12 , 26 ], with pangolin or civet as one of the possible intermediate hosts, and humans are the ultimate hosts [ 27 ]. It is worth noting that a recent study isolated one coronavirus from a Malayan pangolin showing 100, 98.6, 97.8, and 90.7% amino acid identity with SARS-CoV-2 in the E, M, N and S genes, respectively, and the receptor-binding domain within the S protein of the Pangolin-CoV is virtually identical to that of SARS-CoV-2, with only one noncritical amino acid difference. This suggests that SARS-CoV-2 might have originated from the recombination of a Pangolin-CoV-like virus with a Bat-CoV-RaTG13-like virus [ 28 ]. However, more research is required to confirm this.

Routes of transmission

SARS-CoV is transmitted through close-up droplets and contact, while SARS-CoV-2 has a wider range of transmission routes. In addition to short-distance droplet transmission and contact transmission, SARS-CoV-2 can also be transmitted through aerosols in the enclosed space and urine, and mother-to-child transmission may also exist [ 29 , 30 , 31 ]. The Chinese Center for Disease Control and Prevention isolated the SARS-CoV-2 strain from a feces sample of a confirmed patient in Heilongjiang Province, indicating that SARS-CoV-2 can survive in the stool; it has been demonstrated that after intragastric administration of SARS-CoV-2, transgenic mice that express human ACE2 can get the infection and show related pathological changes [ 32 ]. This suggests that fecal-oral transmission may also be one of its transmission modes [ 29 , 33 ].

Susceptible population

The population is generally susceptible to SARS-CoV, mostly young adults; and people are also generally susceptible to SARS-CoV-2. Epidemiological analysis shows that 77.8% of patients with COVID-19 are between 30 and 69 years of age, with the highest proportion in the 50 to 60 years age group, while the infection rate of children is relatively low [ 8 , 34 ].

It is generally believed that SARS-CoV-2 has a stronger propagation capability than SARS-CoV. A previous study showeed basic reproduction number (R 0 ) was 2.9 [ 35 , 36 ]. Based on the epidemiological data of 425 patients, another study showed the basic reproduction number R0 of this new coronary pneumonia to be 2.20 [ 37 , 38 ]. Moreover, there is a study that predicts the R0 value of SARS-CoV-2 to be 3.28 [ 39 ]. Yang et al. [ 40 ] predicted the R 0 to be 3.77—higher than SARS-CoV—but because of the uncertainty, the accuracy of the estimate is limited. The latest research shows that the R 0 of SARS-CoV-2 is about 2.68, which is roughly similar to the R0 reported by World Health Organization (WHO) and the Chinese Center for Disease Control and Prevention [ 41 , 42 ]. SARS-CoV-2 is highly contagious and up to June 17, 2020, SARS-CoV-2 infection had occurred in as many as 216 countries and the cumulative number of COVID-19 patients globally had reached 8,061,550, according to the data from WHO.

SARS-CoV-2 spreads easily but it is less lethal. The mortality rate of SARS-CoV-2 was lower than that of SARS-CoV. Studies have shown that approximately 23 to 32% of patients with SARS will develop severe disease and are prone to death [ 43 ]. A report by WHO shows that 774 of 8098 SARS patients died, with a case fatality rate of 9.6%. In elderly patients, case fatality rate was up to 50% [ 36 ]. SARS-CoV-2 has a wider range of transmission than SARS-CoV or MERS-CoV, and infects a larger number of patients, but the ratio of critically ill COVID-19 patients is relatively lower. Epidemiological characteristics of more than 70,000 cases described that 80.9% COVID-19 patients presented mild/moderate illness. Meanwhile, the crude death rate of COVID-19 was 2.3% and the death rate was 0.015/10 person-days [ 34 ], much lower than the mortality rates of SARS [ 44 ]. Severe illness and death are more common in older patients with underlying conditions. Meanwhile, SARS-CoV-2 not only affects the lungs, but also the heart and kidneys, causing multiple organ failure. Consequently, therapy for severe COVID patients is more difficult than that for SARS.

Origin and evolution

During the widespread epidemic of SARS-CoV-2 in the world, analysis of the SARS-CoV-2 genomic system evolution network revealed three variants, which the researchers tentatively named A, B, and C. Among them, A is an ancestor type; B is derived from A through two mutations of the synonymous mutation T8782C and the non-synonymous mutation C28144T, which is derived from A. The difference between type C and its parent type B is the non-synonymous mutation G26144T, and this mutation converts glycine to valine. Notably, the different types have different geographical distributions in the world. A and C mainly exist in Europe and the United States, while B mainly exists in East Asia, suggesting that Wuhan, the first outbreak spot of type B SARS-CoV-2 may not be the origin of SARS-CoV-2. This provides a new idea for the origin and evolution of SARS-CoV-2 [ 45 ].

Pathological characteristics

Autopsy results in SARS patients suggest that SARS-CoV infection causes severe pulmonary edema, pulmonary congestion, hilar lymphadenopathy, and spleen shrinkage in general [ 46 , 47 ]. Histological features of patients with SARS include bronchial epithelial exfoliation, loss of cilia and squamous metaplasia, diffuse alveolar damage, formation of hyaline membranes, and severe fibrosis of the lung tissue. SARS-CoV can be detected in lymphocytes, monocytes, lymphoid tissues, and respiratory tract as well as in intestinal mucosa, renal tubular epithelial cells, and neurons [ 48 , 49 ].

Certain pathological characteristics of COVID-19 patients have been identified. Pulmonary pathological results attained by Tian et al. [ 50 ] suggested that the early pathological changes induced by SARS-CoV-2 pneumonia include pathological interstitial pneumonia and prominent pulmonary edema, with protein exudation and minor inflammatory cell infiltration. Xu et al. [ 51 ] performed a case dissection on a patient and the results showed that bilateral diffuse alveolar damage with cellular fibromyxoid exudates and hyaline membrane formation corresponded to acute respiratory distress symptoms (ARDS); moreover, the overall pathological characteristics of the lung were similar in SARS and MERS. Inflammatory infiltration of lymphocyte-dominated mononuclear cells and other viral cytopathic-like changes were seen in the lung, but no intranuclear or intracytoplasmic viral inclusions were found. Minor inflammatory infiltration of mononuclear cells was present in the myocardial interstitium and the existence of viral myocarditis could not be ruled out, but no obvious damage to the myocardium was found. Based on the pathology report of one particular patient, the impact of SARS-CoV-2 on the cardiovascular system cannot be determined; hence, additional sample research and analysis are necessary. Another autopsy of a COVID-19 patient in China found that mucus exudation was more obvious than that in SARS patients and lung damage involving diffuse alveolar damage and pulmonary hyaline membrane formation was serious. Histopathologic changes seen on postmortem transthoracic needle biopsies from a COVID-19 patient with hypertension and diabetes showed diffuse alveolar damage. Virus was more highly detected in alveolar epithelial cells, while viral protein expression was low in blood vessels or in the interstitial areas [ 52 ]. A recent pathological study of African American patients found that in addition to diffuse alveolar injury, inflammatory cell infiltration, and hyaline membrane formation, COVID-19 patients also have thrombi in peripheral small vessels with obvious bleeding in the lungs, while no obvious thrombus was found in other organs, including kidney, spleen, pancreas, and liver. At the same time, it was reported that there are a large number of CD61 + megakaryocytes in the alveolar capillaries, and a large number of platelets are actively produced. The large aggregation of platelets and fibrin deposition may jointly promote the production of thrombi within peripheral small vessels in lungs [ 53 ]. However, evidence of damage to other organs and/or systems requires more substantial autopsy results.

The differences between SARS-CoV and SARS-CoV-2 are shown in Table  1 .

Pathogenic mechanisms of SARS-CoV-2

As in SARS-CoV, the S protein of SARS-CoV-2 aids in cell invasion by binding to ACE2 receptors on the host cell surface, causing a series of lung injury responses [ 54 ].

SARS-CoV-2-induced direct damage

When SARS-CoV-2 invades the human body, the RBD on the S1 subunit of the S protein binds to ACE2 expressed on the host cell surface. Subsequently the conformation of the S protein undergoes a significant structural rearrangement, resulting in shedding of the S1 subunit and transition of the S2 subunit to a highly stable post-fusion conformation, which in turn mediates the fusion of the virus with the host cell membrane and cell entry [ 2 ]. After entering the cell, SARS-CoV-2 multiplies and eventually lyses the host cell, causing extensive alveolar damage and ARDS in infected patients.

Down-regulation of ACE2

In addition to mediating the entry of SARS-CoV and SARS-CoV-2 into host cells, ACE2 is also an important mediator of inflammation in the human body. It is mainly expressed in the small intestine, testis, adipose tissue, kidney, heart and thyroid, and lung tissue in the human body, and is also expressed in relatively low amounts in the colon, liver, bladder and adrenal glands, blood, spleen, bone marrow, brain, blood vessels, and muscles [ 55 ]. ACE2 is an enzyme that converts angiotensin (Ang) I to Ang 1–9, Ang II to Ang 1–7, and the latter can interact with MAS receptors, thereby inhibiting the harmful vasodilation and pro-fibrosis mediated by the AT1 receptor and mediating a variety of beneficial negative feedback regulation [ 56 ]. A lack of ACE2 will increase the levels of the two Ang peptides, thereby activating the Ang AT 1 and AT 2 receptors expressed on the surface of alveolar epithelium, vascular endothelium, intestinal epithelium, and kidney cells. During the fusion of the viral envelope with the host cell membrane and cell entry, ACE2 is internalized accordingly due to its binding to the virus, thereby down regulating ACE2 on the cell surface [ 56 ]. The dysregulation of the ACE2-Ang II-AT1 receptor axis and the ACE2-Ang1–7-Mas receptor axis is an important cause of endothelial cell damage, inflammation, and thrombosis [ 55 ].

Immune dysfunction

The disturbance of the immune system is also one of the factors that contributes to tissue and cell damage in patients with COVID-19. In both COVID-19 patients and animal models of SARS-CoV-2 infection, significant inflammatory cell infiltration, increased inflammatory mediators, thickened alveolar septa, and significant vascular system damage have been observed [ 32 ]. At present, pathological reports indicate that severe immune injury is an important pathogenic mechanism of SARS-CoV-2.

• Cytokine storm

A large number of studies have shown that the progression of severe COVID-19 patients is closely related to the massive production and activation of cytokines and inflammatory mediators. The inflammatory response is strong during SARS-CoV-2 infection, and the uncontrolled inflammation of the lungs caused by it may be the main cause of death in some cases. Intensive care unit (ICU) patients have higher levels of interleukin (IL)-1β, IL-1Ra, IL-7, IL-8, IL-9, IL-10, basic FGF, GCSF, GM-CSF, IFN-γ, CXCL10, CCL2, CCL3, CCL4, PDGF, TNF-α, and VEGF in the plasma than healthy controls, and higher levels of IL-2, IL-7, IL-10, GCSF, CXCL10, CCL2, CCL3, and TNF than non-ICU patients [ 57 ]. In addition, neutrophils, elevated D-dimers, and blood urea nitrogen were found in deceased patients infected with COVID-19, suggesting that death may be the result of cytokine storms, inflammatory responses, and acute kidney injury [ 58 ]. Nlrp3γ inflammasome, as a powerful pro-inflammatory system in the body, is also an important cause of cytokine storm. Nlrp3γ is expressed in many cells, including immune, endothelial, hematopoietic, lung epithelial, kidney, and heart cells. High levels of Ang II may over-activate Nlrp3γ in these cells and trigger an immune response through intracellular caspase-1, thereby releasing a large number of inflammatory factors, such as IL-1β and IL-18, and creating gasdermin D pore channels in cell membranes to mediate the release of several biologically active danger-associated molecular pattern molecules, finally mediating cell apoptosis and lysis [ 56 ].

Activation of complement system

The complement system is also involved in immune injury in COVID-19 patients. In the peripheral blood mononuclear cells of COVID-19 patients, the genes related to complement activation are enriched, and the serum complement levels in patients with severe COVID-19 are higher than those in mild cases and healthy controls, indicating that complement-mediated immune injury may be one of the causes of cell damage and aggravation of the disease in patients with COVID-19 [ 59 , 60 ]. Mannose-binding lectin (MBL), a pattern recognition protein present in serum can be combined with MBL-associated serine protease 2 (MASP-2) to initiate the complement-activated lectin pathway by binding to sugar molecules on the surface of pathogens. The SARS-CoV-2 N protein can interact with MASP-2, inducing MASP-2 to automatically activate and cleave complement protein C4 [ 59 ]. Massive deposition of MBL, MASP-2, and C3 and C4 lysates (C4a, C4d) in lung tissue and the membrane attack complex formed with C5b-9 can cause damage and lysis of alveolar cells.

Lymphocyte dysfunction

Lymphopenia, a common feature in patients with COVID-19, was identified in a patient by flow cytometry while lymphocytes were found to be over-activated. This potentially constitutes a key factor related to disease severity and mortality. The number of CD4 + and CD8 + T cells in the peripheral blood of patients was greatly reduced, while a higher number of double positive HLA-DR and CD38 suggested the activation of T cells. In addition, the number of CCR4 + CCR6 + Th17 cells with a high pro-inflammatory effect was increased and CD8 + T cells had a high concentration of cytotoxic granules including perforin and granulysin. Over-activation of T cells characterized by an increase in Th17 and high cytotoxicity of CD8 + T cells could partially explain the severe immune damage in SARS-CoV-2-infected patients. Viral infection rarely caused a Th17 response, but over-activation of Th17/CD8 was detected in patients with COVID-19 requiring medical attention.

However, the latest research indicates that patients with severe COVID-19 also have impaired cytotoxic lymphocyte killing function [ 61 ]. All subtypes of lymphocytes in patients with COVID-19 are reduced, including T cells, B cells, and NK cells. In quantitative analysis of CD4 + and CD8 + T cells at different stages of maturity [ 61 ], it was found that compared with healthy subjects, the frequency of TEMRA (CD45RA + CCR7 − ) and senescent CD8 + T cells (CD57 + ) in COVID-19 patients was significantly higher. However, Tem (CD45RA7 − CCR77 − ) and HLA-DR + CD8 + T cells did not show related changes compared with healthy subjects, exhibiting a skewing of CD8 + T cells towards a terminally differentiated/senescent phenotype; similar findings were also observed for CD4 + T cells. Research on NK cells showed that, in addition to a reduced number of the cells in patients with COVID-19, their ability to produce IFN-α, perforin, and granzymes was also reduced, leading to an impaired virus clearance function. IL-6 may play a major role in the process of the dysfunction of NK cell [ 61 , 62 ]. In patients with severe COVID-19, the decrease in NK cells and their dysfunction are significantly inversely proportional to the level of IL-6 in the serum, while anti-IL-6 receptor monoclonal antibody tocilizumab treatment is able to reverse this process, suggesting that high levels of IL-6 exposure can down-regulate the expression of perforin and granzyme in NK cell. In conclusion, the senescence of CD4 + and CD8 + T cells as well as the impaired function of NK cells can lead to the evasion of SARS-CoV-2 from the immune attack and clearance in patients with severe COVID-19.

Clinical manifestations

Basic clinical characteristics of covid-19.

SARS-CoV-2 infection causes systemic and respiratory symptoms such as fever, muscle soreness, cough, and dyspnea. Guan et al. [ 30 ] collected data of 1099 confirmed COVID-19 patients from 552 hospitals in 30 provinces, autonomous regions, and municipalities in China and demonstrated that cough (67.8%) is the most common symptom among patients, while only 43.8% of patients were diagnosed with fever. ARDS, respiratory failure, multiple organ dysfunction syndrome, as well as septic shock, metabolic acidosis, and coagulation dysfunction were found to manifest in severe cases. Meanwhile, nausea, vomiting, diarrhea, and other gastrointestinal symptoms as well as chest pain, heart palpitations, and other cardiovascular symptoms can also be the first symptoms in patients with COVID-19. Laboratory tests show normal or decreased peripheral blood leukocytes, reduced lymphocyte counts, and abnormalities in liver enzymes, myocardial enzymes, and C-reactive protein. In severe cases, increases in D-dimer and inflammatory factors are detected. Computerized tomography showed that ground-glass opacity is the most common radiologic characteristic and “paving stone sign” may appear in the advanced stage [ 63 , 64 ]. At present, the diagnosis is primarily based on the pathogenic examination of nucleic acid detection. However, nucleic acid detection is subject to factors such as material selection, which may cause a certain false negative rate. Therefore, patients presenting epidemiological characteristics, clinical manifestations, and typical imaging characteristics with negative nucleic acid detection are classified as clinically confirmed cases that must be treated in isolation in the clinic.

COVID-19 and CVD

Many studies report that patients with COVID-19 often have comorbidities—commonly CVD. Based on the published data in China, the prevalence of CVD in COVID-19 patients varied from 1% [ 65 ] to 39% [ 66 ]. CDC COVID-19 Response Team analyzed the data from 50 U.S. states, four U.S. territories, and affiliated islands and showed that 9.0% of patients were suffering from CVD [ 67 ]. Buckner et al. [ 68 ], however, demonstrated that the ratio reached to 38% in Washington State. Mehra et al. [ 69 ] enrolled 8910 patients with COVID-19 from 169 hospitals in Asia, Europe, and North America and showed that 10.2% of the patients had coronary artery disease. Meta-analysis confirmed considerable prevalence of CVD among COVID-19 patients. Li et al. [ 70 ] reported that the prevalence of cardia-cerebrovascular diseases in COVID-19 patients was 16.4% and another study [ 71 ] showed 11.9% of patients with COVID-19 also had CVD. Various proportions of COVID-19 patients with CVD have been singled out due to selection bias and different data samples. It is also worth noting that various definitions of CVD were used in the different studies. For example, some studies recognized coronary heart disease and heart failure as CVD, while some also included cerebrovascular disease and hypertension. Therefore, these results should be cautiously interpreted [ 72 ]. Broader data analysis with uniform definition for CVD remains necessary to determine the proportion of COVID-19 patients with CVD.

CVD is regarded as a risk factor of COVID-19 progression and is associated with higher risk of mortality of patients with COVID-19. A previous cross-sectional study reported that COVID-19 patients with CVD and hypertension were more likely to be transferred to the ICU [ 58 ]. Furthermore, the co-incidence of COVID-19 with coronary heart disease (5.8% vs. 1.8%) was higher in patients with severe COVID-19 than in non-severe patients [ 30 ]. Studies [ 73 , 74 ] found that CVD was associated with disease severity(OR = 3.14; 95% CI 2.32–4.24; OR = 2.74; 95% CI 1.50–5.00) and also the higher prevalence of CVD in critical/mortal COVID-19 patients compared to the non-critical group was shown(OR = 4.78, 95% CI = 2.71–8.42) in another latest study [ 75 ]. The Chinese Center for Disease Control and Prevention announced that the crude mortality of COVID-19 was approximately 0.9%, while in patients with CVD, it rose to 10.5%. Zhang et al. [ 74 ] enrolled 541 patients with COVID-19 and showed the mortality of patients with CVD reached to 22.2%. Presence of CVD was associated with higher mortality (OR = 4.85, 95% CI 3.07–7.70). These studies suggest that more intensive medical care should be provided to patients with COVID-19 having CVD to prevent disease progression and poor prognosis [ 76 ].

COVID-19 and myocardial injury

Myocardial injury is one of the most common complications in patients with COVID-19, especially those in severe condition, with rates reported variously and often indicating a poor prognosis. The prevalence of patients with myocardial injury complication varies from 7.2% [ 58 ] to 27.8% [ 77 ]. In our upcoming meta-analysis, 7 studies were included and the analysis indicated that the pooled prevalence of myocardial injury complication in COVID-19 patients is 17.0%. In addition, myocardial injury is more commonly seen in severe cases. Huang et al. [ 57 ] and Wang et al. [ 58 ] demonstrated that the incidence of myocardial injury was 30.7 and 22.2%, respectively. Li et al. [ 78 ] showed that the ratio was 34.9% in severe patients. Moreover, it has been proved that myocardial injury is associated with higher risk of in-hospital mortality. The mortality was 51.2% in myocardial injury group, while that in patients without myocardial injury was 4.5% (P < 0.001) [ 79 ]. Similar results were also demonstrated in other studies [ 80 , 81 , 82 ]. Although the specific mechanisms by which SARS-CoV-2 causes myocardial injury remain unclear, they may be related to the following:

Direct damage Due to the wide expression of ACE2 receptors in cardiomyocytes, a large number of SARS-CoV-2 may directly invade cardiomyocytes through binding to the receptor, which may cause the cardiac damage. Besides, replication and reproduction of SARS-CoV-2 rely on substrates in cardiomyocytes, which may lead to abnormal metabolism of cardiomyocytes and consequent damage.

Down-regulation of ACE2 Levels of Ang II, an inflammatory factor regulatory protein, are elevated by SARS-CoV-2 infection, leading to the production of reactive oxygen species and oxidative stress injury of myocardial cells [ 83 , 84 ]. After Ang II recognizes the AT 1 receptor, several kinases, including extracellular regulated protein kinases 1/2, c-Jun N-terminal kinase/signal transducer and activator of transcription, calcium kinase II and protein kinase C, are also activated. In addition, the down-regulation of ACE2 caused by SARS-CoV-2 activates the ADAM-17/TACE pathway, which leads to increased release of TNF-α and subsequent myocardial inflammatory damage [ 85 , 86 ]. However, changes in the content of Ang II and ACE2, the initiating factors, and the specific molecular mechanisms that damage the body, require further study.

Immune damage and cytokine storm Similar to SARS-CoV and MERS-CoV, SARS-CoV-2 induces the release of a large number of cytokines, causing a cytokine storm that damages myocardial cells [ 87 ]. TNF-α, produced by activated macrophages, may be a main chemokine in patients with COVID-19, causing the release of a series of pro-inflammatory factors that also plays an essential role in myocardial damage [ 88 ]. The specific molecular mechanisms involving immune damage and cytokine storms with myocardial damage must be studied further.

Oxygen supply-demand imbalance. Pulmonary pathology suggests that SARS-CoV-2 infection is mainly due to exudative changes, leading to hypoxemia or respiratory failure. In addition, patients with COVID-19 have systemic symptoms such as fever, leading to increased oxygen demand, which further exacerbates the imbalance between oxygen supply and demand. Mitochondrial damage and oxidative stress induced by the imbalance between oxygen supply and demand are important pathophysiological mechanisms of cardiac damage caused by viral infection [ 89 , 90 ]. It is speculated that myocardial damage induced by SARS-CoV-2 may also be related to oxidative stress. Mitochondrial structure and function are dysfunctional under hypoxic conditions, the production of antioxidant substances is reduced, and the level of reactive oxygen species is increased, which induces myocardial damage. In addition, endoplasmic reticulum stress induced by hypoxia promotes increase of pro-apoptotic factors and expression of apoptosis gene through activation of PERK-ATF4-CHOP (protein kinase R-like endoplasmic reticulum kinase-transcription activator 4-C/EBP homologous protein) pathway, thereby inducing cardiomyocyte apoptosis and myocardial injury [ 91 ]. The different mechanisms of myocardial injury induced by SARS-CoV-2 are shown in Fig.  2 .

Potential mechanisms of myocardial injury induced by SARS-CoV-2. a SARS-CoV-2 damages cardiomyocytes directly; b SARS-CoV-2 infection reduces ACE2 thus AngII is up-regulated. Kinases in cardiomyocytes are activated to induce an inflammation effect causing myocardial injury; c Inflammatory cytokines release; d Oxygen supply-demand imbalance

COVID-19 and VTE

SARS-CoV-2-induced hypercoagulability and VTE have received great attention recently [ 92 , 93 ]. Middeldorp et al. [ 94 ] showed that 19.6% pf patients with COVID-19 show VTE complication. Llitjos et al. [ 95 ], Klok et al. [ 96 ], and Cui SP et al. [ 97 ] demonstrated that the prevalence of VTE was up to 69.2, 27, and 24.7%, respectively, in ICU-COVID-19 patients. It has been shown that the level of D-dimer is higher in COVID-19 patients [ 98 ]. Compared with the non-severe patients of COVID-19, a higher proportion of elevated D-dimer was observed among severe cases [ 99 , 100 ] and higher level of D-dimer is one of the risk factors for disease progression [ 101 , 102 , 103 ]. Besides, higher concentrations of D-dimer (aHR = 1.10 [1.01–1.19] per decile increase) were independently associated with in-hospital mortality [ 104 ]. A retrospective cohort study also demonstrated that D-dimer > 1 μg/mL on admission was associated with higher risk of death (OR = 18.4, 95% CI: 2.6–128.6, p = 0.003) [ 105 ]. SARS-CoV-2 induces endothelial injury and cytokine storm may explain the appearance of VTE and elevated D-dimer in COVID-19 patients [ 106 , 107 ] while the exact molecular mechanisms still need to be elucidated. In clinics, VTE and dynamic changes in D-dimer levels should be considered to prevent the clinical deterioration of patients with COVID-19.

COVID-19 therapy

Treatment of COVID-19 patients is fully discussed nowadays and with worldwide researchers’ efforts, effective therapy strategies are shared to improve the prognosis of patients with COVID-19. Therapies including medicine, specific immunotherapy and cell therapy are expected to play an effective role in treating COVID-19 patients. Here, based on recent research and/or Chinese experience, we comprehensively introduce some effective treatments of patients with COVID-19.

Medicine therapy

Traditional chinese medicine (tcm).

TCM shows encouraging results in improving symptoms and decreasing the deterioration, mortality, and recurrence rates of COVID-19. In China, 91.5% of patients with COVID-19 have used TCM and efficiency exceeded 90%. Chinese scholars have proposed that TCM can modulate the dysfunction of ACE2 caused by viral infection in multiple pathways. Moreover, it can inhibit ribosomal proteins to obstruct viral replication, conferring a protective effect in humans. Additionally, TCM inhibits the excessive production of activated cytokines and eliminates the inflammatory response by regulating Th17 and cytokine-related pathways, which may provide protective effects in COVID-19 patients. A recent study showed that 8 core herbal combinations and 10 new formulae were regarded as potentially useful candidates for COVID-19 treatment [ 108 ]. Lianhuaqingwen capsule, which is a repurposed marketed Chinese herb product has been confirmed for influenza treatment. A prospective multicenter open-label randomized controlled trial [ 109 ] proved that it could also be considered to ameliorate clinical symptoms of COVID-19 after 14 days of use. However, further assessment through double blind and longer follow-up duration trials is necessary.

Chloroquine and Hydroxychloroquine

Chloroquine and hydroxychloroquine are used for treating malaria and whether they can be a potential drug for COVID-19 treatment is currently controversial. A previous study showed that the use of chloroquine in 100 COVID-19 patients was potentially able to inhibit the virus and it was suggested to be used in clinical treatment in Chinese guideline. Hydroxychloroquine, as an analog of chloroquine, was shown to have a stronger inhibitory effect on SARS-CoV-2 than chloroquine in vitro experiments with a higher safety. In addition, low-dose hydroxychloroquine may also play an immunoregulatory role in severely infected patients who cannot use glucocorticoids and immunosuppressants, and relieve the cytokine storm [ 110 ]. Conversely, a recent study demonstrated that there was no evidence for the efficacy of chloroquine or hydroxychloroquine against COVID-19. Furthermore, it increased the risk of serious cardiac complications and mortality of patients. However, because of the high dose of chloroquine or hydroxychloroquine used in this study as well as suspicion on data sources and data consistency, these results cannot be used to reach consensus. Notably, the article was retracted by Lancet [ 111 ]. Thus, the clinical value of repurposing these drugs for COVID-19 therapy still requires further investigation and high-quality research.

Remdesivir, an adenosine nucleotide analogue prodrug having broad-spectrum antiviral activity, is expected to become a potent drug for COVID-19 [ 112 ]. However, two recent randomized controlled trials showed contradictory results. A Chinese study [ 113 ] enrolled 237 severe COVID-19 patients and demonstrated that compared with the placebo group, no improvement in mortality was found after taking remdesivir for 28 days (13.9% versus 12.8%). This study failed to complete full enrollment due to the end of the disease outbreak and 2:1 randomization in trial, leading to lower inspection efficiency, both of which may decrease credibility of the conclusion. A larger American study [ 114 ], which included 1063 patients with COVID-19, demonstrated that remdesivir was effective for treatment. It showed that median recovery time in remdesivir group was 11 days compared to 15 days in the placebo group (P < 0.001), and 14-day mortality was 7.1 and 11.9% in remdesivir group and placebo group, respectively. Researchers are optimistic regarding the use of remdesivir for COVID-19 treatment, although more clinical trials are required to provide strong evidence.

Lopinavir/ritonavir

Lopinavir/Ritonavir, a kind of viral replication inhibitor, was used for SARS patients [ 115 ] and it may be effective for SARS-CoV-2 infection. A recent randomized, controlled, open-label trial [ 116 ] included 199 patients with COVID-19 and showed that the time to clinical improvement between lopinavir-ritonavir group and standard-care group was not different (HR = 1.31, 95% CI: 0.95 to 1.80). Besides, 28-day mortality was similar in the two groups, while gastrointestinal adverse events were more common in COVID-19 patients treated with lopinavir/ritonavir at 400/100 mg twice daily. The trial showed disappointing results with lopinavir/ritonavir. However, patients in this study were at the late stage in infection and tissue damage had already appeared, while viral replication inhibitor is more effective in early infection, which may explain inefficacy of the treatment. In addition, Baden et al. [ 117 ] also pointed out that the concentration of the drug used in patients failed to inhibit viral replication and both groups were heterogeneous, which may lead to inaccurate conclusion. Therefore, future high-quality blind randomized clinical trials should be carried out to examine the efficacy of lopinavir/ritonavir against COVID-19.

Immunomodulatory therapy

There is much attention recently on the use of dexamethasone, tocilizumab and anakinra for COVID-19. In a large RECOVERY trial [ 118 ], 2100 COVID-19 patients were enrolled for evaluating the efficacy of dexamethasone for treatment. Surprisingly, it showed that dexamethasone was able to reduce mortality by up to one third in hospitalised patients with severe complication. Dexamethasone, a cheap and widely available steroid, has such a large effect on reducing mortality of COVID-19 patients and it is expected to be an effective and affordable drug for treatment. Tocilizumab, the first IL-6 receptor inhibitor has a significant effect on the treatment of COVID-19 patients. A study [ 119 ] demonstrated that tocilizumab improved the clinical outcome in severe and critical patients and it has been recommended to use in severe COVID-19 patients in China. Recently, some randomized controlled trials are being launched, which will provide a more comprehensive knowledge on the use of tocilizumab in COVID-19 patients. A retrospective study [ 120 ] with 29 COVID-19 patients found that respiratory function was improved among 72% COVID-19 patients after using high-dose anakinra. Another study [ 121 ] which enrolled 8 severe COVID-19 patients with secondary hemophagocytic lymphohistiocytosis also showed the benefits of respiratory function after taking anakinra. However, lager randomized controlled trials are needed to verify the efficacy and safety of anakinra on COVID-19 patients treatment.

Specific immunotherapy

Vaccination.

COVID-19 vaccine including nucleic acid vaccine (including mRNA vaccine, DNA vaccine), recombinant genetic engineering (protein recombinant) vaccine, inactivated vaccine, attenuated influenza virus vector vaccine, and adenovirus vector vaccine are yet to be explored [ 122 , 123 ]. Faced with SARS-CoV-2 infection, global scientific researchers are stepping up the development of vaccines. Coronavirus glycoproteins are potential vaccine targets for SARS-CoV and MERS-CoV. Due to the lack of immunological research on SARS-CoV-2 and its similarity with SARS-CoV, most studies use SARS-CoV immune information to assist the development of a SARS-CoV-2 vaccine. Cytotoxic T-lymphocyte cell epitopes and B cell epitopes on the surface of SARS-CoV-2 are potential targets for the SARS-CoV-2 vaccine [ 124 ]. Some researchers think that the entire S protein or the S1 protein containing the RBD is an antigen that can be used for vaccine development [ 125 ]; however, some studies have pointed out that vaccines targeting antibodies against S2 linear epitopes may be more effective, because of less genetic mismatches rendering SARS-CoV-derived antibodies ineffective compared with S1 subunit [ 126 ].

After the outbreak of SAR-CoV-2, at least 37 biopharmaceutical companies or academic institutions have used multiple platforms including mRNA, DNA, adenoviral vectors, and recombinant proteins to develop preventive vaccines [ 125 ]. In China, 5 vaccines (1 for adenovirus vector vaccine, 4 for inactivated vaccines) are under phase II clinical trials. Recently, Zhu et al. [ 127 ] published the first inspiring clinical result of vaccine in human. In this dose-escalation, single-center, open-label, non-randomized, phase 1 trial of an Ad5 vectored COVID-19 vaccine, all 108 participants showed immune response after vaccination. From day 14 post-vaccination, rapid specific T-cell responses were found and peak of humoral immunity against SARS-CoV-2 appeared on day 28 post-vaccination. It suggested that the Ad5 vectored COVID-19 vaccine was worth further exploration. Besides, nucleic acid-based vaccines constitute the most advanced strategy in the development of new pathogen vaccines. With the recent improvements in the stability and efficiency of protein translation and the optimization of delivery systems such as lipid nanoparticles (LNPs), nucleic acid vaccines (including DNA and RNA vaccines) are a promising approach that needs further investigation [ 128 , 129 ]. However, vaccine-mediated harmful immune responses, the time and cost of research and development, the availability of large-scale production, and the ownership and management of vaccines will all be huge challenges that need to be overcome, and strengthening international cooperation is essential for accelerating research to develop new coronavirus vaccines.

Passive immunity

Injection of monoclonal antibodies is important for the short-term prevention of viral infections and it is used as an effective treatment upon viral infection. The SARS monoclonal antibody targets the S protein RBD on the SARS-CoV envelope. The RBDs in SARS-CoV-2 and SARS-CoV exhibit homology, prompting speculation that SARS monoclonal antibody is effective against COVID-19. A previous study determined that SARS monoclonal antibody CR3022 bound to the SARS-CoV-2 RBD and the epitope of CR3022 in SARS-CoV-2 RBD did not overlap with the ACE2 binding site. It was believed that CR3022—either alone or in combination with other neutralizing antibodies—might act as a therapeutic candidate for the prevention and treatment of SARS-CoV-2 infection. However, some of the strongest SARS-CoV-specific neutralizing antibodies (such as M396 and CR3014) failed to bind to the SARS-CoV-2 spike protein, establishing that differences in the RBD influenced the cross-reactivity of neutralizing antibodies [ 130 ]. It is vital to develop a new monoclonal antibody that can specifically bind to the SARS-CoV-2 RBD.

For patients with rapid disease progression, passive plasma therapy is an effective treatment. WHO recommends the use of convalescent plasma or serum to treat COVID-19 when vaccines or effective antiviral drugs are not available. In China, immune plasma therapy has been clinically effective for patients with severe COVID [ 131 ]. However, a randomized clinical trial [ 132 ] enrolled 103 patients with severe or life-threatening COVID-19 and showed that compared with the standard treatment group, there was no advancement in time to clinical improvement within 28 days after convalescent plasma therapy. This study was terminated early and was an open-label study, which may be underpowered to explore the differences in result. Further research is expected to provide a more accurate evaluation.

Antibody-dependent enhancement is common in various viruses [ 133 ] and it is a focus for vaccine design and passive immunization. Both SARS-CoV and MERS-CoV RBD-specific neutralizing antibodies can mediate antibody-dependent enhancement effects [ 134 ]. Whether SARS-CoV-2 exhibits an antibody-dependent enhancement effect remains to be investigated.

Cell therapy

Cell therapy is expected to emerge as a new way to fight SARS-CoV-2; indeed, projects on stem cell therapy for COVID-19 have been established in China (ChiCTR2000030020). Mesenchymal stem cells have immunomodulatory effects based on their location at the site of inflammation, regulating inflammation-related cytokines and reducing inflammation [ 135 ]. Via paracrine cytokines, they are expected to inhibit the cytokine storm and the overwhelming immune response caused by SARS-CoV-2. Consequently, alveolar epithelial cells and vascular endothelial cells are protected. NK cells can also improve human immunity and exert effective antiviral effects. Recently, Food and Drug Administration approved the use of mesenchymal stem cells to treat severe COVID-19 patients and clinical trial of mesenchymal stem cells in the treatment of COVID-19 has also launched in the UK. However, mesenchymal stem cells and NK cells still have a long way to go before their routine use in clinics.

The outbreak of COVID-19 induced by SARS-CoV-2 has gained much attention worldwide. By June 17, 2020, SARS-CoV-2 infection cases have occurred in as many as 216 countries, areas or territories, and a total of 8,061,550 cases have been confirmed; the scientists are now concentrated on researching the virus for a comprehensive understanding and for the development of preventive and management measures. Here, we summarized the differences between SARS-CoV-2 and SARS-CoV with regards to classification, amino acid composition and protein structure, and epidemiological and pathological characteristics. The pathogenic mechanisms of SARS-CoV-2 have been also discussed. Based on our expertise, we have focused on CVD in patients with COVID-19 and myocardial injury and VTE induced by SARS-CoV-2. Meanwhile, the information of potential medicines and therapies including TCM, chloroquine and hydroxychloroquine, remdesivir, lopinavir/ritonavir and immunomodulatory therapy, and specific immunotherapies and cell therapy have been summarized.

Availability of data and materials

Not applicable.

Abbreviations

Coronavirus disease 2019

Open reading frames

Non-structural proteins

Receptor binding domain

Angiotensin converting enzyme2

World Health Organization

Basic reproduction number

Acute respiratory distress syndrome

Interleukin

• Cardiovascular disease
• Venous thromboembolism

Traditional Chinese medicine

Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, Pan P, Wang W, Hu D, Liu X, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92:424–32.

Article   CAS   Google Scholar  

Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, Duan G. Virology, Epidemiology, Pathogenesis, and Control of COVID-19. Viruses. 2020;12.

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet (London, England). 2020;395:565–74.

Woo PCY, Lau SKP, Lam CSF, Lau CCY, Tsang AKL, Lau JHN, Bai R, Teng JLL, Tsang CCC, Wang M, et al. Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J Virol. 2012;86:3995–4008.

Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019;17:181–92.

Mahase E. Coronavirus covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate. BMJ (Clinical research ed). 2020;368:m641.

Google Scholar  

Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382:727–33.

Liu J, Zheng X, Tong Q, Li W, Wang B, Sutter K, Trilling M, Lu M, Dittmer U, Yang D. Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV. J Med Virol. 2020;92(5):491–4.

Lancet T. Emerging understandings of 2019-nCoV. Lancet (London, England) . 2020;395:311.

Article   Google Scholar  

Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, Zhong W, Hao P. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Science China Life sciences; 2020.

Horton R. Offline: 2019-nCoV outbreak-early lessons. Lancet (London, England). 2020;395:322.

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W, Si H, Zhu Y, Li B, Huang C, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020.

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020.

Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, Lu G, Qiao C, Hu Y, Yuen KY, et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020.

Klenk HD, Garten W. Host cell proteases controlling virus pathogenicity. Trends Microbiol. 1994;2:39–43.

Steinhauer DA. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology. 1999;258:1–20.

Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh C-L, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (New York, NY). 2020;367:eabb2507.

Yan R, Zhang Y, Guo Y, Xia L, Zhou Q. Structural basis for the recognition of the 2019-nCoV by human ACE2. bioRxiv. 2020;956946.

Chan J, Kok K, Zhu Z, Chu H, To K, Yuan S, Yuen K. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect. 2020;9:221–236.

Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature; 2020.

Tang X, Wu C, Li X, Song Y, Yao X, Wu X, Duan Y, Zhang H, Wang Y, Qian Z, et al. On the origin and continuing evolution of SARS-CoV-2. Natl Sci Rev. 2020;7:1012–3.

Su YC, Anderson DE, Young BE, Zhu F, Linster M, Kalimuddin S, Low JG, Yan Z, Jayakumar J, Sun L, et al. Discovery of a 382-nt deletion during the early evolution of SARS-CoV-2. bioRxiv. 2020;2020.2003.2011:987222.

Luk HKH, Li X, Fung J, Lau SKP, Woo PCY. Molecular epidemiology, evolution and phylogeny of SARS coronavirus. Infect Genet Evol. 2019;71:21–30.

Li X, Zai J, Zhao Q, Nie Q, Li Y, Foley BT, Chaillon A. Evolutionary history, potential intermediate animal host, and cross-species analyses of SARS-CoV-2. J Med Virol; 2020.

Du Z, Xu X, Wu Y, Wang L, Cowling BJ, Meyers LA. Serial Interval of COVID-19 among Publicly Reported Confirmed Cases. Emerg Infect Dis. 2020;26.

Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrob Agents 2020:105924.

Lam TT-Y, Shum MH-H, Zhu H-C, Tong Y-G, Ni X-B, Liao Y-S, Wei W, Cheung WY-M, Li W-J, Li L-F, et al: Identification of 2019-nCoV related coronaviruses in Malayan pangolins in southern China. bioRxiv 2020:2020.2002.2013.945485.

Xiao K, Zhai J, Feng Y, Zhou N, Zhang X, Zou JJ, Li N, Guo Y, Li X, Shen X, et al. Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins. Nature; 2020.

Lu C, Liu X, Jia Z. 2019-nCoV transmission through the ocular surface must not be ignored. Lancet (London, England); 2020.

Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, Liu L, Shan H, Lei C, Hui DSC, et al. clinical characteristics of coronavirus disease 2019 in China. N Engl J Med; 2020.

Nishiura H, Linton NM, Akhmetzhanov AR. Initial Cluster of Novel Coronavirus (2019-nCoV) Infections in Wuhan, China Is Consistent with Substantial Human-to-Human Transmission. J Clin Med. 2020;9.

Sun SH, Chen Q, Gu HJ, Yang G, Wang YX, Huang XY, Liu SS, Zhang NN, Li XF, Xiong R, et al. A mouse model of SARS-CoV-2 infection and pathogenesis. Cell Host Microbe; 2020.

ES A: Potential fecal transmission of SARS-CoV-2: current evidence and implications for public health. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2020, 95:363–370.

[The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China]. Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi 2020, 41:145–151.

CM P, LM C, YH G, CO B: Comparing nonpharmaceutical interventions for containing emerging epidemics. Proc Natl Acad Sci U S A 2017, 114:4023–4028.

Stadler K, Masignani V, Eickmann M, Becker S, Abrignani S, Klenk HD, Rappuoli R. SARS--beginning to understand a new virus. Nat Rev Microbiol. 2003;1:209–218.

Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong J, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. The New England journal of medicine; 2020.

Riou J, Althaus CL. pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. 2020;25.

Liu Y, Gayle AA, Wilder-Smith A, Rocklöv J. The reproductive number of COVID-19 is higher compared to SARS coronavirus. Journal of travel medicine; 2020.

Yang Y, Lu Q, Liu M, Wang Y, Zhang A, Jalali N, Dean N, Longini I, Halloran ME, Xu B, et al: Epidemiological and clinical features of the 2019 novel coronavirus outbreak in China. medRxiv 2020:2020.2002.2010.20021675.

Hellewell J, Abbott S, Gimma A, Bosse NI, Jarvis CI, Russell TW, Munday JD, Kucharski AJ, Edmunds WJ, Centre for the Mathematical Modelling of Infectious Diseases COVID-19 Working Group, Funk S, Eggo RM. Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts. Lancet Glob Health. 2020;8:e488-e496.

Chen T, Rui J, Wang Q, Zhao Z, Cui J, Yin L. A mathematical model for simulating the phase-based transmissibility of a novel coronavirus. Infectious diseases of poverty. 2020;9:24.

Venkataraman T, Frieman MB. The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis. Antivir Res .2017;143:142–150.

Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A novel coronavirus emerging in China - key questions for impact assessment. N Engl J Med. 2020;382:692–694.

Forster P, Forster L, Renfrew C, Forster M. Phylogenetic network analysis of SARS-CoV-2 genomes. Proc Natl Acad Sci U S A. 2020;117:9241–9243.

Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, Chu CM, Hui PK, Mak KL, Lim W. Lung pathology of fatal severe acute respiratory syndrome. Lancet (London, England). 2003;361:1773–1778.

Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, Cai J, Li X, Kang W, Weng D, et al. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol. 2003;200:282–289.

Bradley BT, Bryan A. emerging respiratory infections: the infectious disease pathology of SARS, MERS, pandemic influenza, and legionella. Semin Diagn Pathol. 2019;36:152–159.

Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, Zou W, Zhan J, Wang S, Xie Z, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005;202:415–424.

Tian S, Hu W, Niu L, Liu H, Xu H, Xiao S-Y. Pulmonary pathology of early phase SARS-COV-2 pneumonia; 2020.

Book   Google Scholar  

Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;S2213–2600(2220):30076–X.

Zhang H, Zhou P, Wei Y, Yue H, Wang Y, Hu M, Zhang S, Cao T, Yang C, Li M, et al. Histopathologic Changes and SARS-CoV-2 Immunostaining in the Lung of a Patient With COVID-19. Annals of internal medicine; 2020.

Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, Vander Heide RS. pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Respir Med; 2020.

Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. Journal of virology; 2020.

Verdecchia P, Cavallini C, Spanevello A, Angeli F. COVID-19: ACE2centric infective disease? Hypertension (Dallas, Tex : 1979); 2020.

Ratajczak MZ, Kucia M. SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells. Leukemia; 2020.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England). 2020;395:497–506.

Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA; 2020.

McKechnie JL, Blish CA. The innate immune system: fighting on the front lines or fanning the flames of COVID-19? Cell host & microbe; 2020.

YXiong Y, Liu Y, Cao L, Wang D, Guo M, Jiang A, Guo D, Hu W, Yang J, Tang Z, et al. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerging microbes & infections. 2020;9:761–770.

Mazzoni A, Salvati L, Maggi L, Capone M, Vanni A, Spinicci M, Mencarini J, Caporale R, Peruzzi B, Antonelli A, et al. Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent. The Journal of clinical investigation ; 2020.

Cifaldi L, Prencipe G, Caiello I, Bracaglia C, Locatelli F, De Benedetti F, Strippoli R. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis & rheumatology (Hoboken, NJ) . 2015;67:3037–3046.

Chung M, Bernheim A, Mei X, Zhang N, Huang M, Zeng X, Cui J, Xu W, Yang Y, Fayad ZA et al. CT Imaging Features of 2019 Novel coronavirus (2019-nCoV). Radiology. 2020:200230.

Lei J, Li J, Li X, Qi X. CT Imaging of the 2019 Novel coronavirus (2019-nCoV) pneumonia. Radiology. 2020:200236.

Lian J, Jin X, Hao S, Cai H, Zhang S, Zheng L, Jia H, Hu J, Gao J, Zhang Y, et al. Analysis of Epidemiological and Clinical features in older patients with Corona Virus Disease 2019 (COVID-19) out of Wuhan. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America ; 2020.

Li J, Wang X, Chen J, Zhang H, Deng A. Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China. JAMA cardiology ; 2020.

Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 - United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:382–6.

Buckner FS, McCulloch DJ, Atluri V, Blain M, McGuffin SA, Nalla AK, Huang ML, Greninger AL, Jerome KR, Cohen SA, et al. clinical features and outcomes of 105 hospitalized patients with COVID-19 in Seattle, Washington. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America; 2020.

Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med; 2020.

Li B, Yang J, Zhao F, Zhi L, Wang X, Liu L, Bi Z, Zhao Y. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clinical research in cardiology : official journal of the German Cardiac Society. 2020;109:531–538.

Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, Alvarado-Arnez LE, Bonilla-Aldana DK, Franco-Paredes C, Henao-Martinez AF, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623.

Tadic M, Cuspidi C, Mancia G, Dell'Oro R, Grassi G. COVID-19, hypertension and cardiovascular diseases: Should we change the therapy? Pharmacological research. 2020;158:104906.

Aggarwal G, Cheruiyot I, Aggarwal S, Wong J, Lippi G, Lavie CJ, Henry BM, Sanchis-Gomar F, et al. Association of Cardiovascular Disease With Coronavirus Disease 2019 (COVID-19) Severity: A Meta-Analysis. Curr Probl Cardiol. 2020:100617.

Zhang J, Lu S, Wang X, Jia X, Li J, Lei H, Liu Z, Liao F, Ji M, Lv X, et al. Do underlying cardiovascular diseases have any impact on hospitalised patients with COVID-19? Heart (British Cardiac Society ) ; 2020.

Varikasuvu SR, Dutt N. cardiovascular disease as a risk factor of disease progression in COVID-19: the corrected effect size and forest plot. The Journal of infection; 2020.

Chatterjee NA, Cheng RK. Cardiovascular disease and COVID-19: implications for prevention, surveillance and treatment. Heart (British Cardiac Society); 2020.

Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, Wang H, Wan J, Wang X, Lu Z. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA cardiology; 2020.

Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, Shi J, Zhou M, Wu B, Yang Z, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. The Journal of allergy and clinical immunology; 2020.

Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA cardiology; 2020.

Ni W, Yang X, Liu J, Bao J, Li R, Xu Y, Guo W, Hu Y, Gao Z. Acute Myocardial Injury at Hospital Admission is Associated with All-cause Mortality in COVID-19. J Am College Cardiol; 2020.

Aikawa T, Takagi H, Ishikawa K, Kuno T. Myocardial injury characterized by elevated cardiac troponin and in-hospital mortality of COVID-19: an insight from a meta-analysis. J Med Virol; 2020.

Li X, Guan B, Su T, Liu W, Chen M, Bin Waleed K, Guan X, Gary T, Zhu Z. Impact of cardiovascular disease and cardiac injury on in-hospital mortality in patients with COVID-19: a systematic review and meta-analysis. Heart (British Cardiac Society); 2020.

Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res. 2008;102:488–496.

Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Gordijn SJ, Bolling MC, Dijkstra G, Voors AA, Osterhaus AD, et al. Angiotensin-converting enzyme-2 (ACE2), SARS-CoV-2 and pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol; 2020.

Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417:822–828.

Oudit GY, Kassiri Z, Patel MP, Chappell M, Butany J, Backx PH, Tsushima RG, Scholey JW, Khokha R, Penninger JM. Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice. Cardiovasc Res. 2007;75:29–39.

Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev; 2020.

Li L, Zhou Q, Xu J. Myocardial injury and COVID-19: possible mechanisms. Life Sci. 2020;253:117723.

Wei J, Gao D, Wang H, Yan R, Liu Z, Yuan Z, Liu J, Chen M. Impairment of myocardial mitochondria in viral myocardial disease and its reflective window in peripheral cells. PLoS One. 2014;9:e116239.

Li Y, Ge L, Yang P, Tang J, Lin J, Chen P, Guan X. Carvedilol treatment ameliorates acute coxsackievirus B3-induced myocarditis associated with oxidative stress reduction. Eur J Pharmacol. 2010;640:112–116.

Durante W. Targeting endoplasmic reticulum stress in hypoxia-induced cardiac injury. Vasc Pharmacol. 2016;83:1–3.

Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033–2040.

Al-Samkari H, KarpLeaf RS, Dzik WH, Carlson JC, Fogerty AE, Waheed A, Goodarzi K, Bendapudi P, Bornikova L, Gupta S, et al. COVID and coagulation: bleeding and thrombotic manifestations of SARS-CoV2 infection. Blood; 2020.

Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Müller MCA, Bouman CCS, Beenen LFM, Kootte RS, Heijmans J, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thrombosis Haemostasis; 2020.

Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, Auvray M, Merouani K. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thrombosis Haemostasis; 2020.

Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145–147.

Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thrombosis Haemostasis. 2020;18:1421–1424.

Han H, Yang L, Liu R, Liu F, Wu K, Li J, Liu X, Zhu C. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med; 2020.

Zhang J, Dong X, Cao Y, Yuan Y, Yang Y, Yan Y, Akdis CA, Gao Y. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy; 2020.

Liu X, Li Z, Liu S, Sun J, Chen Z, Jiang M, Zhang Q, Wei Y, Wang X, Huang Y, et al. Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19. Acta pharmaceutica Sinica B; 2020.

Dong Y, Zhou H, Li M, Zhang Z, Guo W, Yu T, Gui Y, Wang Q, Zhao L, Luo S, et al. A novel simple scoring model for predicting severity of patients with SARS-CoV-2 infection. Transboundary Emerg Dis; 2020.

Petrilli CM, Jones SA, Yang J, Rajagopalan H, O'Donnell L, Chernyak Y, Tobin KA, Cerfolio RJ, Francois F, Horwitz LI. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ (Clinical research ed). 2020;369:m1966.

Sun Y, Dong Y, Wang L, Xie H, Li B, Chang C, Wang F. Characteristics and prognostic factors of disease severity in patients with COVID-19: The Beijing experience. J Autoimmun. 2020:102473.

Cummings MJ, Baldwin MR, Abrams D, Jacobson SD, Meyer BJ, Balough EM, Aaron JG, Claassen J, Rabbani LE, Hastie J. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet (London, England); 2020.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (London, England). 2020;395:1054–1062.

Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. New Engl J Med; 2020.

Thachil J, Agarwal S. Understanding the COVID-19 coagulopathy spectrum. Anaesthesia; 2020.

Luo L, Jiang J, Wang C, Fitzgerald M, Hu W, Zhou Y, Zhang H, Chen S. Analysis on herbal medicines utilized for treatment of COVID-19. Acta Pharm Sin B. 2020.

Hu K, Guan W, Bi Y, Zhang W, Li L, Zhang B, Liu Q, Song Y, Li X, Duan Z, et al. Efficacy and Safety of Lianhuaqingwen Capsules, a repurposed Chinese Herb, in Patients with Coronavirus disease 2019: A multicenter, prospective, randomized controlled trial. Phytomedicine. 2020:153242.

Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis; 2020.

Mehra MR, Ruschitzka F, Patel AN. Retraction-Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. 2020;395:1820.

Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother. 2020;64:e00399–20.

Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet (London, England). 2020;395:1569–1578.

Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S. Remdesivir for the treatment of Covid-19 - preliminary report. N Engl J Med; 2020.

Chu C, Cheng V, Hung I, Wong M, Chan K, Chan K, Kao R, Poon L, Wong C, Guan Y, et al. role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59:252–256.

Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020;382:1787–1799.

Baden LR, Rubin EJ. Covid-19 - the search for effective therapy. N Engl J Med. 2020;382:1851–2.

Ledford H. Coronavirus breakthrough: dexamethasone is first drug shown to save lives. NEWS. [ https://www.nature.com/articles/d41586-020-01824-5 ].

Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117:10970–10975.

Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M, Canetti D, Oltolini C, Castiglioni B, Tassan Din C, Boffini N, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatology. 2020;2:e325-e331.

Dimopoulos G, de Mast Q, Markou N, Theodorakopoulou M, Komnos A, Mouktaroudi M, Netea MG, Spyridopoulos T, Verheggen RJ, Hoogerwerf J, et al. Favorable Anakinra Responses In Severe Covid-19 Patients With Secondary Hemophagocytic Lymphohistiocytosis. Cell Host Microbe; 2020.

Lu S. Timely development of vaccines against SARS-CoV-2. Emerg Microbes Infect. 2020;9:542–4.

Callaway E. The race for coronavirus vaccines: a graphical guide. Nature. 2020;580:576–7.

Baruah V, Bose S. Immunoinformatics-aided identification of T cell and B cell epitopes in the surface glycoprotein of 2019-nCoV. J Med Virol. 2020;92:495.

Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020;38:1–9.

Ahmed SF, Quadeer AA, McKay MR. Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies. Viruses. 2020;12.

Zhu FC, Li YH, Guan XH, Hou LH, Wang WJ, Li JX, Wu SP, Wang BS, Wang Z, Wang L, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet (London, England); 2020.

Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 2018;17:261–279.

Maruggi G, Zhang C, Li J, Ulmer JB, Yu D. mRNA as a transformative Technology for Vaccine Development to control infectious diseases. Mol Ther. 2019;27:757–72.

Tian X, Li C, Huang A, Xia S, Lu S, Shi Z, Lu L, Jiang S, Yang Z, Wu Y, Ying T. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect. 2020;9:382–385.

Zhang L, Liu Y. Potential Interventions for Novel Coronavirus in China: A Systematic Review. Journal of medical virology; 2020.

Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, Kong Y, Ren L, Wei Q, Mei H, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA; 2020.

Yang Y, Lyu T, Zhou R, He X, Ye K, Xie Q, Zhu L, Chen T, Shen C, Wu Q, et al. The Antiviral and Antitumor Effects of Defective Interfering Particles/Genomes and Their Mechanisms. Front Microbiol. 2019;10:1852.

Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, He L, Chen Y, Wu J, Shi Z, et al. Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. J Virol. 2020;94 e02015.

Kong T, Park JM, Jang JH, Kim CY, Bae SH, Choi Y, Jeong YH, Kim C, Chang SW, Kim J, et al. Immunomodulatory effect of CD200-positive human placenta-derived stem cells in the early phase of stroke. Exp Mol Med. 2018;50:e425.

Wu JT, Leung K, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet (London, England). 2020;395:689–697.

Giandhari J, Pillay S, Wilkinson E, Tegally H, Sinayskiy I, Schuld M, Lourenço J, Chimukangara B, Lessells RJ, Moosa Y, et al. Early transmission of SARS-CoV-2 in South Africa: An epidemiological and phylogenetic report. medRxiv. 2020.

Chow CC, Chang JC, Gerkin RC, Vattikuti S. Global prediction of unreported SARS-CoV2 infection from observed COVID-19 cases. medRxiv; 2020.

Davies NG, Kucharski AJ, Eggo RM, Gimma A, Edmunds WJ. Effects of non-pharmaceutical interventions on COVID-19 cases, deaths, and demand for hospital services in the UK: a modelling study. Lancet Public Health; 2020.

World Health Organization: Coronavirus disease (COVID-19) outbreak situation [ https://www.who.int/emergencies/diseases/novel-coronavirus-2019 ].

Sharma A, Tiwari S, Deb MK, Marty JL. Severe Acute Respiratory Syndrome Coronavirus −2 (SARS-CoV-2): A global pandemic and treatments strategies. Int J Antimicrob Agents. 2020;106054.

COVID-19, Australia: epidemiology report 16 (reporting week to 23:59 AEST 17 May 2020). Communicable diseases intelligence. 2018;2020:44.

Undela K, Gudi SK. Assumptions for disparities in case-fatality rates of coronavirus disease (COVID-19) across the globe. Eur Rev Med Pharmacol Sci. 2020;24:5180–2.

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Acknowledgements

This research was funded by the [National Key R&D Program of China] under Grant [number 2018YFC1602206]; [Yangjiang Science and Technology Program key projects] under Grant [number 2019010]; [Guangzhou Science and Technology Program key projects] under Grant [number 201803040006] and [Guangdong Science and Technology Program key projects] under Grant [number 2018B020207006].

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Toxic: How the search for the origins of COVID-19 turned politically poisonous

FILE - A security person moves journalists away from the Wuhan Institute of Virology after a World Health Organization team arrived for a field visit in Wuhan in China’s Hubei province on Feb. 3, 2021. The hunt for COVID-19 origins has gone dark in China. An AP investigation drawing on thousands of pages of undisclosed emails and documents and dozens of interviews found feuding officials and fear of blame ended meaningful Chinese and international efforts to trace the virus almost as soon as they began, despite years of public statements to the contrary. (AP Photo/Ng Han Guan, File)

FILE - A volunteer looks out near a Chinese national flag during a farewell ceremony for the last group of medical workers who came from outside Wuhan to help the city during the coronavirus outbreak in Wuhan in central China’s Hubei province on April 15, 2020. The hunt for COVID-19 origins has gone dark in China. An AP investigation drawing on thousands of pages of undisclosed emails and documents and dozens of interviews found feuding officials and fear of blame ended meaningful Chinese and international efforts to trace the virus almost as soon as they began, despite years of public statements to the contrary. (AP Photo/Ng Han Guan, File)

FILE - A farewell ceremony is held for the last group of medical workers who came from outside Wuhan to help the city during the coronavirus outbreak in Wuhan in central China’s Hubei province on April 15, 2020. The hunt for COVID-19 origins has gone dark in China. An AP investigation drawing on thousands of pages of undisclosed emails and documents and dozens of interviews found feuding officials and fear of blame ended meaningful Chinese and international efforts to trace the virus almost as soon as they began, despite years of public statements to the contrary. (AP Photo/Ng Han Guan, File)

FILE - A policeman moves journalists back from a farewell event held for the last group of medical workers who came from outside Wuhan to help the city during the coronavirus outbreak in Wuhan in central China’s Hubei province on April 15, 2020. The hunt for COVID-19 origins has gone dark in China. An AP investigation drawing on thousands of pages of undisclosed emails and documents and dozens of interviews found feuding officials and fear of blame ended meaningful Chinese and international efforts to trace the virus almost as soon as they began, despite years of public statements to the contrary. (AP Photo/Ng Han Guan, File)

FILE - A security guard waves for journalists to clear the road after a convoy carrying the World Health Organization team entered the Huanan Seafood Market on the third day of a field visit in Wuhan in central China’s Hubei province on Jan. 31, 2021. The hunt for COVID-19 origins has gone dark in China. An AP investigation drawing on thousands of pages of undisclosed emails and documents and dozens of interviews found feuding officials and fear of blame ended meaningful Chinese and international efforts to trace the virus almost as soon as they began, despite years of public statements to the contrary. (AP Photo/Ng Han Guan, File)

FILE - A photographer on a tall ladder tries to take photos of the World Health Organization convoy after it entered the Huanan Seafood Market on the third day of field visit in Wuhan in central China’s Hubei province on Jan. 31, 2021. The hunt for COVID-19 origins has gone dark in China. An AP investigation drawing on thousands of pages of undisclosed emails and documents and dozens of interviews found feuding officials and fear of blame ended meaningful Chinese and international efforts to trace the virus almost as soon as they began, despite years of public statements to the contrary. (AP Photo/Ng Han Guan, File)

FILE - Marion Koopmans, right, and Peter Ben Embarek, center, of the World Health Organization team say farewell to their Chinese counterpart Liang Wannian, left, after a WHO-China Joint Study Press Conference at the end of the WHO mission in Wuhan, China, on Feb. 9, 2021. The hunt for COVID-19 origins has gone dark in China. An AP investigation drawing on thousands of pages of undisclosed emails and documents and dozens of interviews found feuding officials and fear of blame ended meaningful Chinese and international efforts to trace the virus almost as soon as they began, despite years of public statements to the contrary. (AP Photo/Ng Han Guan, File)

FILE - Peter Ben Embarek of a World Health Organization team attends a joint press conference at the end of their mission to investigate the origins of the coronavirus pandemic in Wuhan in central China’s Hubei province on Feb. 9, 2021. The hunt for COVID-19 origins has gone dark in China. An AP investigation drawing on thousands of pages of undisclosed emails and documents and dozens of interviews found feuding officials and fear of blame ended meaningful Chinese and international efforts to trace the virus almost as soon as they began, despite years of public statements to the contrary. (AP Photo/Ng Han Guan, File)

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BEIJING (AP) — The hunt for the origins of COVID-19 has gone dark in China, the victim of political infighting after a series of stalled and thwarted attempts to find the source of the virus that killed millions and paralyzed the world for months.

The Chinese government froze meaningful domestic and international efforts to trace the virus from the first weeks of the outbreak, despite statements supporting open scientific inquiry, an Associated Press investigation found. That pattern continues to this day, with labs closed, collaborations shattered, foreign scientists forced out and Chinese researchers barred from leaving the country.

The investigation drew on thousands of pages of undisclosed emails and documents and dozens of interviews that showed the freeze began far earlier than previously known and involved political and scientific infighting in China as much as international finger-pointing.

As early as Jan. 6, 2020, health officials in Beijing closed the lab of a Chinese scientist who sequenced the virus and barred researchers from working with him.

Scientists warn the willful blindness over coronavirus’ origins leaves the world vulnerable to another outbreak, potentially undermining pandemic treaty talks coordinated by the World Health Organization set to culminate in May.

At the heart of the question is whether the virus jumped from an animal or came from a laboratory accident. A U.S. intelligence analysis says there is insufficient evidence to prove either theory, but the debate has further tainted relations between the U.S. and China.

Unlike in the U.S., there is virtually no public debate in China about whether the virus came from nature or from a lab leak. In fact, there is little public discussion at all about the source of the disease, first detected in the central city of Wuhan.

Crucial initial efforts were hampered by bureaucrats in Wuhan trying to avoid blame who misled the central government; the central government, which muzzled Chinese scientists and subjected visiting WHO officials to stage-managed tours; and the U.N. health agency itself, which may have compromised early opportunities to gather critical information in hopes that by placating China, scientists could gain more access, according to internal materials obtained by AP.

In a faxed statement, China’s Foreign Ministry defended China’s handling of research into the origins, saying the country is open and transparent , shared data and research, and “made the greatest contribution to global origins research.” The National Health Commission, China’s top medical authority, said the country “invested huge manpower, material and financial resources” and “has not stopped looking for the origins of the coronavirus.”

It could have played out differently, as shown by the outbreak of SARS , a genetic relative of COVID-19, nearly 20 years ago. China initially hid infections then, but WHO complained swiftly and publicly. Ultimately, Beijing fired officials and made reforms. The U.N. agency soon found SARS likely jumped to humans from civet cats in southern China and international scientists later collaborated with their Chinese counterparts to pin down bats as SARS’ natural reservoir.

But different leaders of both China and WHO, China’s quest for control of its researchers, and global tensions have all led to silence when it comes to searching for COVID-19’s origins. Governments in Asia are pressuring scientists not to look for the virus for fear it could be traced inside their borders.

Even without those complications, experts say identifying how outbreaks begin is incredibly challenging and that it’s rare to know with certainty how some viruses begin spreading.

“It’s disturbing how quickly the search for the origins of (COVID-19) escalated into politics,” said Mark Woolhouse, a University of Edinburgh outbreak expert. “Now this question may never be definitively answered.”

A security person moves journalists away from the Wuhan Institute of Virology after a World Health Organization team arrived for a field visit in Wuhan in China’s Hubei province on Feb. 3, 2021. (AP Photo/Ng Han Guan, File)

CLOUDS OF SECRECY

Secrecy clouds the beginning of the outbreak. Even the date when Chinese authorities first started searching for the origins is unclear.

The first publicly known search for the virus took place on Dec. 31, 2019, when Chinese Center for Disease Control scientists visited the Wuhan market where many early COVID-19 cases surfaced.

However, WHO officials heard of an earlier inspection of the market on Dec. 25, 2019, according to a recording of a confidential WHO meeting provided to AP by an attendee. Such a probe has never been mentioned publicly by either Chinese authorities or WHO.

In the recording, WHO’s top animal virus expert, Peter Ben Embarek, mentioned the earlier date, describing it as “an interesting detail.” He told colleagues that officials were “looking at what was on sale in the market, whether all the vendors have licenses (and) if there was any illegal (wildlife) trade happening in the market.”

A colleague asked Ben Embarek, who is no longer with WHO, if that seemed unusual. He responded that “it was not routine,” and that the Chinese “must have had some reason” to investigate the market. “We’ll try to figure out what happened and why they did that.”

Ben Embarek declined to comment. Another WHO staffer at the Geneva meeting in late January 2020 confirmed Ben Embarek’s comments.

The Associated Press could not confirm the search independently. It remains a mystery if it took place, what inspectors discovered, or whether they sampled live animals that might point to how COVID-19 emerged.

Peter Ben Embarek of a World Health Organization team attends a joint press conference at the end of their mission to investigate the origins of the coronavirus pandemic in Wuhan in China’s Hubei on Feb. 9, 2021. (AP Photo/Ng Han Guan, File)

A Dec. 25, 2019, inspection would have come when Wuhan authorities were aware of the mysterious disease. The day before, a local doctor sent a sample from an ill market vendor to get sequenced that turned out to contain COVID-19. Chatter about the unknown pneumonia was spreading in Wuhan’s medical circles, according to one doctor and a relative of another who declined to be identified, fearing repercussions.

A scientist in China when the outbreak occurred said they heard of a Dec. 25 inspection from collaborating virologists in the country. They declined to be named out of fear of retribution.

WHO said in an email that it was “not aware” of the Dec. 25 investigation. It is not included in the U.N. health agency’s official COVID-19 timeline .

When China CDC researchers from Beijing arrived on Jan. 1 to collect samples at the market, it had been ordered shut and was already being disinfected, destroying critical information about the virus. Gao Fu, then head of the China CDC, mentioned it to an American collaborator.

“His complaint when I met him was that all the animals were gone,” said Columbia University epidemiologist Ian Lipkin.

Marion Koopmans, right, and Peter Ben Embarek, center, of the World Health Organization team say farewell to their Chinese counterpart Liang Wannian, left, after a WHO-China Joint Study Press Conference at the end of the WHO mission in Wuhan, China, on Feb. 9, 2021. (AP Photo/Ng Han Guan, File)

Robert Garry, who studies viruses at Tulane University, said a Dec. 25 probe would be “hugely significant,” given what is known about the virus and its spread.

“Being able to swab it directly from the animal itself would be pretty convincing and nobody would be arguing” about the origins of COVID-19, he said.

But perhaps local officials simply feared for their jobs, with memories of firings after the 2003 SARS outbreak still vivid, said Ray Yip, the founding head of the U.S. Centers for Disease Control and Prevention outpost in China.

“They were trying to save their skin, hide the evidence,” Yip said.

The Wuhan government did not respond to a faxed request for comment.

Another early victim was Zhang Yongzhen, the first scientist to publish a sequence of the virus . A day after he wrote a memo urging health authorities to action, China’s top health official ordered Zhang’s lab closed.

“They used their official power against me and our colleagues,” Zhang wrote in an email provided to AP by Edward Holmes, an Australian virologist.

On Jan. 20, 2020, a WHO delegation arrived in Wuhan for a two-day mission. China did not approve a visit to the market, but they stopped by a China CDC lab to examine infection prevention and control procedures, according to an internal WHO travel report. WHO’s then-China representative, Dr. Gauden Galea, told colleagues in a private meeting that inquiries about COVID-19’s origins went unanswered.

By then, many Chinese were angry at their government . Among Chinese doctors and scientists, the sense grew that Beijing was hunting for someone to blame.

“There are a few cadres who have performed poorly,” Chinese leader Xi Jinping said in unusually harsh comments in February . “Some dare not take responsibility, wait timidly for orders from above, and don’t move without being pushed.”

The government opened investigations into top health officials, according to two former and current China CDC staff and three others familiar with the matter. Health officials were encouraged to report colleagues who mishandled the outbreak to Communist Party disciplinary bodies, according to two of the people.

Some people both inside and outside China speculated about a laboratory leak. Those suspicious included right-wing American politicians , but also researchers close to WHO.

The focus turned to the Wuhan Institute of Virology, a high-level lab that experimented with some of the world’s most dangerous viruses.

In early February 2020, some of the West’s leading scientists, headed by Dr. Jeremy Farrar, then at Britain’s Wellcome Trust, and Dr. Anthony Fauci, then director of the U.S. National Institutes of Health, banded together to assess the origins of the virus in calls, a Slack channel and emails.

They drafted a paper suggesting a natural evolution, but even among themselves, they could not agree on the likeliest scenario. Some were alarmed by features they thought might indicate tinkering.

“There have (been) suggestions that the virus escaped from the Wuhan lab,” Holmes, the Australian virologist, who believed the virus originated in nature, wrote in a Feb. 7, 2020, email. “I do a lot of work in China, and I can (assure) you that a lot of people there believe they are being lied to.”

American scientists close to researchers at the Wuhan Institute of Virology warned counterparts there to prepare.

James LeDuc, head of a Texas lab, emailed his Wuhan colleague on Feb. 9, 2020, saying he’d already been approached by U.S. officials. “Clearly addressing this will be essential, with any kind of documentation you might have,” he wrote.

The Chinese government was conducting its own secret investigation into the Wuhan Institute. Gao, the then-head of the China CDC, and another Chinese health expert revealed its existence in interviews months and years later . Both said the investigation found no evidence of wrongdoing, which Holmes, the Australian virologist, also heard from another contact in China. But Gao said even he hadn’t seen further details , and some experts suspect they may never be released.

WHO started negotiations with China for a further visit with the virus origins in mind, but it was China’s Foreign Ministry that decided the terms.

Scientists were sidelined and politicians took control. China refused a visa for Ben Embarek, then WHO’s top animal virus expert. The itinerary dropped nearly all items linked to an origins search, according to draft agendas for the trip obtained by the AP. And Gao, the then-head of the China CDC who is also a respected scientist tasked with investigating the origins, was left off the schedule.

Instead, Liang Wannian, a politician in the Communist Party hierarchy, took charge of the international delegation. Liang is an epidemiologist close to top Chinese officials and China’s Foreign Ministry who is widely seen as pushing the party line, not science-backed policies , according to nine people familiar with the situation who declined to be identified to speak on a sensitive subject.

Liang ruled in favor of shutting the Wuhan market at the beginning of the outbreak, according to a Chinese media interview with a top China CDC official that was later deleted . Significantly, it was Liang who promoted an implausible theory that the virus came from contaminated frozen food imported into China. Liang did not respond to an emailed request for comment.

Most of the WHO delegation was not allowed to go to Wuhan, which was under lockdown. The few who did learned little. They again had no access to the Wuhan Institute of Virology or the wildlife market and obtained only scant details about China CDC efforts to trace the coronavirus there.

On the train, Liang lobbied the visiting WHO scientists to praise China’s health response in their public report. Dr. Bruce Aylward, a senior adviser to WHO Director-General Tedros Adhanom Ghebreyesus, saw it as the “best way to meet China’s need for a strong assessment of its response.”

The new section was so flattering that colleagues emailed Aylward to suggest he “dial it back a bit.”

“It is remarkable how much knowledge about a new virus has been gained in such a short time,” read the final report, which was reviewed by China’s top health official before it went to Tedros.

As criticism of China grew, the Chinese government deflected blame. Instead of firing health officials, they declared their virus response a success and closed investigations into the officials with few job losses.

“There were no real reforms, because doing reforms means admitting fault,” said a public health expert in contact with Chinese health officials who asked not to be identified because of the sensitivity of the matter.

In late February 2020, the internationally respected doctor Zhong Nanshan appeared at a news conference and said that “the epidemic first appeared in China, but it did not necessarily originate in China.”

A policeman moves journalists back from a farewell event held for the last group of medical workers who came from outside Wuhan to help the city during the coronavirus outbreak in Wuhan in central China’s Hubei province on April 15, 2020. (AP Photo/Ng Han Guan, File)

Days later, Chinese leader Xi ordered new controls on virus research . A leaked directive from China’s Publicity Department ordered media not to report on the virus origins without permission , and a public WeChat account reposted an essay claiming the U.S. military created COVID-19 at a Fort Detrick lab and spread it to China during a 2019 athletic competition in Wuhan. Days later, a Chinese Foreign Ministry spokesperson repeated the accusation .

The false claims enraged U.S. President Donald Trump, who began publicly blaming China for the outbreak, calling COVID-19 “the China virus” and the “kung-flu.”

Chinese officials told WHO that blood tests on lab workers at the Wuhan Institute of Virology were negative, suggesting COVID-19 wasn’t the result of a lab accident there. But when WHO pressed for an independent audit, Chinese officials balked and demanded WHO investigate the U.S. and other countries as well.

By blaming the U.S., Beijing diverted blame. It was effective in China , where many Chinese were upset by racially charged criticism . But outside China, it fueled speculation of a lab leak coverup.

By the time WHO led another visit to Wuhan in January 2021, a year into the pandemic, the atmosphere was toxic.

Liang, the Chinese health official in charge of two earlier WHO visits, continued to promote the questionable theory that the virus was shipped into China on frozen food. He suppressed information suggesting it could have come from animals at the Wuhan market, organizing market workers to tell WHO experts no live wildlife was sold and cutting recent photos of wildlife at the market from the final report. There was heavy political scrutiny, with numerous Chinese officials who weren’t scientists or health officers present at meetings.

Despite a lack of direct access, the WHO team concluded that a lab leak was “extremely unlikely.” So it was infuriating to Chinese officials when WHO chief Tedros said it was “premature” to rule out the lab leak theory, saying such lab accidents were “common,” and pressed China to be more transparent.

China told WHO any future missions to find COVID-19 origins should be elsewhere, according to a letter obtained by AP. Since then, global cooperation on the issue has ground to a halt; an independent group convened by WHO to investigate the origins of COVID-19 in 2021 has been stymied by the lack of cooperation from China and other issues.

Chinese scientists are still under heavy pressure, according to 10 researchers and health officials. Researchers who published papers on the coronavirus ran into trouble with Chinese authorities. Others were barred from travel abroad for conferences and WHO meetings. Gao, the then-director of the China CDC, was investigated after U.S. President Joe Biden ordered a review of COVID-19 data, and again after giving interviews on the virus origins.

New evidence is treated with suspicion. In March 2023, scientists announced that genetic material collected from the market showed raccoon dog DNA mixed with COVID-19 in early 2020, data that WHO said should have been publicly shared years before. The findings were posted, then removed by Chinese researchers with little explanation.

The head of the China CDC Institute of Viral Disease was forced to retire over the release of the market data, according to a former China CDC official who declined to be named to speak on a sensitive topic.

“It has to do with the origins, so they’re still worried,” the former official said. “If you try and get to the bottom of it, what if it turns out to be from China?”

Other scientists note that any animal from which the virus may have originally jumped has long since disappeared.

“There was a chance for China to cooperate with WHO and do some animal sampling studies that might have answered the question,” said Tulane University’s Garry. “The trail to find the source has now gone cold.”

Cheng reported from Geneva.

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NeurIPS 2024

Conference Dates: (In person) 9 December - 15 December, 2024

Homepage: https://neurips.cc/Conferences/2024/

Call For Papers 

Author notification: Sep 25, 2024

Camera-ready, poster, and video submission: Oct 30, 2024 AOE

Submit at: https://openreview.net/group?id=NeurIPS.cc/2024/Conference  

The site will start accepting submissions on Apr 22, 2024 

Subscribe to these and other dates on the 2024 dates page .

The Thirty-Eighth Annual Conference on Neural Information Processing Systems (NeurIPS 2024) is an interdisciplinary conference that brings together researchers in machine learning, neuroscience, statistics, optimization, computer vision, natural language processing, life sciences, natural sciences, social sciences, and other adjacent fields. We invite submissions presenting new and original research on topics including but not limited to the following:

• Applications (e.g., vision, language, speech and audio, Creative AI)
• Deep learning (e.g., architectures, generative models, optimization for deep networks, foundation models, LLMs)
• Evaluation (e.g., methodology, meta studies, replicability and validity, human-in-the-loop)
• General machine learning (supervised, unsupervised, online, active, etc.)
• Infrastructure (e.g., libraries, improved implementation and scalability, distributed solutions)
• Machine learning for sciences (e.g. climate, health, life sciences, physics, social sciences)
• Neuroscience and cognitive science (e.g., neural coding, brain-computer interfaces)
• Optimization (e.g., convex and non-convex, stochastic, robust)
• Probabilistic methods (e.g., variational inference, causal inference, Gaussian processes)
• Reinforcement learning (e.g., decision and control, planning, hierarchical RL, robotics)
• Social and economic aspects of machine learning (e.g., fairness, interpretability, human-AI interaction, privacy, safety, strategic behavior)
• Theory (e.g., control theory, learning theory, algorithmic game theory)

Machine learning is a rapidly evolving field, and so we welcome interdisciplinary submissions that do not fit neatly into existing categories.

Authors are asked to confirm that their submissions accord with the NeurIPS code of conduct .

Formatting instructions:   All submissions must be in PDF format, and in a single PDF file include, in this order:

• The submitted paper
• Technical appendices that support the paper with additional proofs, derivations, or results 
• The NeurIPS paper checklist  

Other supplementary materials such as data and code can be uploaded as a ZIP file

The main text of a submitted paper is limited to nine content pages , including all figures and tables. Additional pages containing references don’t count as content pages. If your submission is accepted, you will be allowed an additional content page for the camera-ready version.

The main text and references may be followed by technical appendices, for which there is no page limit.

The maximum file size for a full submission, which includes technical appendices, is 50MB.

Authors are encouraged to submit a separate ZIP file that contains further supplementary material like data or source code, when applicable.

You must format your submission using the NeurIPS 2024 LaTeX style file which includes a “preprint” option for non-anonymous preprints posted online. Submissions that violate the NeurIPS style (e.g., by decreasing margins or font sizes) or page limits may be rejected without further review. Papers may be rejected without consideration of their merits if they fail to meet the submission requiremhttps://www.overleaf.com/read/kcffhyrygkqc#85f742ents, as described in this document. 

Paper checklist: In order to improve the rigor and transparency of research submitted to and published at NeurIPS, authors are required to complete a paper checklist . The paper checklist is intended to help authors reflect on a wide variety of issues relating to responsible machine learning research, including reproducibility, transparency, research ethics, and societal impact. The checklist forms part of the paper submission, but does not count towards the page limit.

Supplementary material: While all technical appendices should be included as part of the main paper submission PDF, authors may submit up to 100MB of supplementary material, such as data, or source code in a ZIP format. Supplementary material should be material created by the authors that directly supports the submission content. Like submissions, supplementary material must be anonymized. Looking at supplementary material is at the discretion of the reviewers.

We encourage authors to upload their code and data as part of their supplementary material in order to help reviewers assess the quality of the work. Check the policy as well as code submission guidelines and templates for further details.

Use of Large Language Models (LLMs): We welcome authors to use any tool that is suitable for preparing high-quality papers and research. However, we ask authors to keep in mind two important criteria. First, we expect papers to fully describe their methodology, and any tool that is important to that methodology, including the use of LLMs, should be described also. For example, authors should mention tools (including LLMs) that were used for data processing or filtering, visualization, facilitating or running experiments, and proving theorems. It may also be advisable to describe the use of LLMs in implementing the method (if this corresponds to an important, original, or non-standard component of the approach). Second, authors are responsible for the entire content of the paper, including all text and figures, so while authors are welcome to use any tool they wish for writing the paper, they must ensure that all text is correct and original.

Double-blind reviewing:   All submissions must be anonymized and may not contain any identifying information that may violate the double-blind reviewing policy.  This policy applies to any supplementary or linked material as well, including code.  If you are including links to any external material, it is your responsibility to guarantee anonymous browsing.  Please do not include acknowledgements at submission time. If you need to cite one of your own papers, you should do so with adequate anonymization to preserve double-blind reviewing.  For instance, write “In the previous work of Smith et al. [1]…” rather than “In our previous work [1]...”). If you need to cite one of your own papers that is in submission to NeurIPS and not available as a non-anonymous preprint, then include a copy of the cited anonymized submission in the supplementary material and write “Anonymous et al. [1] concurrently show...”). Any papers found to be violating this policy will be rejected.

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Venue home page: https://openreview.net/group?id=NeurIPS.cc/2024/Conference

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Dual submissions: Submissions that are substantially similar to papers that the authors have previously published or submitted in parallel to other peer-reviewed venues with proceedings or journals may not be submitted to NeurIPS. Papers previously presented at workshops are permitted, so long as they did not appear in a conference proceedings (e.g., CVPRW proceedings), a journal or a book.  NeurIPS coordinates with other conferences to identify dual submissions.  The NeurIPS policy on dual submissions applies for the entire duration of the reviewing process.  Slicing contributions too thinly is discouraged.  The reviewing process will treat any other submission by an overlapping set of authors as prior work. If publishing one would render the other too incremental, both may be rejected.

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After the initial response period, authors will be able to respond to any further reviewer/AC questions and comments by posting on the submission’s forum page. The program chairs reserve the right to solicit additional reviews after the initial author response period.  These reviews will become visible to the authors as they are added to OpenReview, and authors will have a chance to respond to them.

After the notification deadline, accepted and opted-in rejected papers will be made public and open for non-anonymous public commenting. Their anonymous reviews, meta-reviews, author responses and reviewer responses will also be made public. Authors of rejected papers will have two weeks after the notification deadline to opt in to make their deanonymized rejected papers public in OpenReview.  These papers are not counted as NeurIPS publications and will be shown as rejected in OpenReview.

Publication of accepted submissions:   Reviews, meta-reviews, and any discussion with the authors will be made public for accepted papers (but reviewer, area chair, and senior area chair identities will remain anonymous). Camera-ready papers will be due in advance of the conference. All camera-ready papers must include a funding disclosure . We strongly encourage accompanying code and data to be submitted with accepted papers when appropriate, as per the code submission policy . Authors will be allowed to make minor changes for a short period of time after the conference.

Contemporaneous Work: For the purpose of the reviewing process, papers that appeared online within two months of a submission will generally be considered "contemporaneous" in the sense that the submission will not be rejected on the basis of the comparison to contemporaneous work. Authors are still expected to cite and discuss contemporaneous work and perform empirical comparisons to the degree feasible. Any paper that influenced the submission is considered prior work and must be cited and discussed as such. Submissions that are very similar to contemporaneous work will undergo additional scrutiny to prevent cases of plagiarism and missing credit to prior work.

Plagiarism is prohibited by the NeurIPS Code of Conduct .

Other Tracks: Similarly to earlier years, we will host multiple tracks, such as datasets, competitions, tutorials as well as workshops, in addition to the main track for which this call for papers is intended. See the conference homepage for updates and calls for participation in these tracks. 

Experiments: As in past years, the program chairs will be measuring the quality and effectiveness of the review process via randomized controlled experiments. All experiments are independently reviewed and approved by an Institutional Review Board (IRB).

Financial Aid: Each paper may designate up to one (1) NeurIPS.cc account email address of a corresponding student author who confirms that they would need the support to attend the conference, and agrees to volunteer if they get selected. To be considered for Financial the student will also need to fill out the Financial Aid application when it becomes available.