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

BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m3862 (Published 23 October 2020) Cite this as: BMJ 2020;371:m3862

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Muge Cevik , clinical lecturer1 2,
Krutika Kuppalli , assistant professoriii,
Jason Kindrachuk , banana professor of virology4,
Malik Peiris , professor of virology5

¹Partition of Infection and Global Wellness Enquiry, School of Medicine, Academy of St Andrews, St Andrews, United kingdom of great britain and northern ireland
²Specialist Virology Laboratory, Royal Infirmary of Edinburgh, Edinburgh, UK and Regional Infectious Diseases Unit, Western Full general Hospital, Edinburgh, UK
^threeDivision of Infectious Diseases, Medical University of Southward Carolina, Charleston, SC, USA
^ivLaboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, Academy of Manitoba, Winnipeg, MB, Canada
⁵Schoolhouse of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Authoritative Region, Cathay

Correspondence to Thousand Cevik mc349{at}st-andrews.ac.u.k.

What you lot demand to know

SARS-CoV-2 is genetically similar to SARS-CoV-1, but characteristics of SARS-CoV-ii—eg, structural differences in its surface proteins and viral load kinetics—may help explicate its enhanced rate of transmission
In the respiratory tract, superlative SARS-CoV-ii load is observed at the fourth dimension of symptom onset or in the beginning calendar week of disease, with subsequent decline thereafter, indicating the highest infectiousness potential but earlier or within the offset five days of symptom onset
Reverse transcription polymerase chain reaction (RT-PCR) tests can detect viral SARS-CoV-two RNA in the upper respiratory tract for a mean of 17 days; all the same, detection of viral RNA does non 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 (one-ii 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 take been reported, and emerging show suggests that these may correlate with severity of affliction but wane over time

Since the emergence of SARS-CoV-2 in December 2019, at that place has been an unparalleled global try to characterise the virus and the clinical course of illness. Coronavirus disease 2019 (covid-19), caused past SARS-CoV-two, follows a biphasic pattern of illness that likely results from the combination of an early viral response phase and an inflammatory second stage. About clinical presentations are balmy, and the typical pattern of covid-19 more resembles an influenza-like disease—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 particular).1 In this review, we provide a broad update on the emerging understanding of SARS-CoV-2 pathophysiology, including virology, manual dynamics, and the allowed response to the virus. Any of the mechanisms and assumptions discussed in the commodity and in our understanding of covid-19 may be revised as further testify emerges.

What nosotros know about the virus

SARS-CoV-ii 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 (Due east), 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 jail cell through its target receptor. The S1 sub-unit of measurement of the S poly peptide contains the receptor binding domain that binds to the peptidase domain of angiotensin-converting enzyme 2 (ACE ii). In SARS-CoV-2 the S2 sub-unit is highly preserved and is considered a potential antiviral target. The virus structure and replication bicycle are described in figure i.

Fig 1

(i) The virus binds to ACE ii as the host target prison cell receptor in synergy with the host'southward transmembrane serine protease 2 (jail 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 (three-7) show the remaining steps of viral replication, leading to viral assembly, maturation, and virus release

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Coronaviruses take the chapters for proofreading during replication, and therefore mutation rates are lower than in other RNA viruses. As SARS-CoV-ii has spread globally information technology has, similar other viruses, accumulated some mutations in the viral genome, which contains geographic signatures. Researchers have examined these mutations to written report virus characterisation and empathise epidemiology and transmission patterns. In general, the mutations accept 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 fabricated with severity of illness equally measured past hospitalisation outcomes.3 These findings have yet to be confirmed with regards to natural infection.

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

SARS-CoV-two has a college reproductive number (R₀) than SARS-CoV-i, 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-two preferentially collaborate with the angiotensin-converting enzyme 2 (ACE ii) receptor, SARS-CoV-two has structural differences in its surface proteins that enable stronger binding to the ACE two receptor4 and greater efficiency at invading host cells.ane SARS-CoV-2 as well has greater affinity (or bonding) for the upper respiratory tract and conjunctiva,5 thus can infect the upper respiratory tract and can bear airways more easily.6

Viral load dynamics and duration of infectiousness

Viral load kinetics could likewise explain some of the differences between SARS-CoV-2 and SARS-CoV-1. In the respiratory tract, peak SARS-CoV-two load is observed at the time of symptom onset or in the first week of illness, with subsequent pass up thereafter, which indicates the highest infectiousness potential but 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 offset week after symptom onset, enabling early instance detection in the community.7

Quantitative opposite transcription polymerase chain reaction (qRT-PCR) technology can discover viral SARS-CoV-2 RNA in the upper respiratory tract for a hateful 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 ix days of illness.five This corresponds to what is known about manual based on contact tracing studies, which is that transmission capacity is maximal in the first week of illness, and that transmission after this menses has not been documented.viii Severely ill or allowed-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 exist express.91011 People with mild symptoms (paucisymptomatic) and those whose symptom have non yet appeared all the same carry big amounts of virus in the upper respiratory tract, which might contribute to the easy and rapid spread of SARS-CoV-2.seven Symptomatic and pre-symptomatic manual (ane to 2 days before symptom onset) is probable to play a greater role in the spread of SARS-CoV-2.1012 A combination of preventive measures, such as concrete distancing and testing, tracing, and self-isolation, continue to exist needed.

Route of transmission and transmission dynamics

Like other coronaviruses, the primary mechanism of transmission of SARS-CoV-ii is via infected respiratory droplets, with viral infection occurring by directly 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 About transmission occurs through shut range contact (such as xv minutes confront to face and inside 2 one thousand),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 go infected within a group of susceptible contacts with a principal case) ranges from 4% to 35%.12 Sleeping in the same room equally, or being a spouse of an infected individual increases the risk of infection, but isolation of the infected person abroad from the family is related to lower take a chance of infection.12 Other activities identified equally high gamble include dining in close proximity with the infected person, sharing nutrient, and taking part in group activities 12 The risk of infection substantially increases in enclosed environments compared with outdoor settings.12 For case, a systematic review of manual 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 >two chiliad).1214151617

The part 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, drinking glass) and at lower temperature and humidity (eg, air conditioned environments).1819 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 ecology contamination. Nevertheless, both SARS-CoV-1 and SARS-CoV-2 are readily inactivated by ordinarily used disinfectants, emphasising the potential value of surface cleaning and handwashing. SARS-CoV-2 RNA has been found in stool samples and RNA shedding oftentimes persists for longer than in respiratory samples7; yet, virus isolation has rarely been successful from the stool.57 No published reports draw faecal-oral manual. 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.twenty It remains to exist seen if similar transmission may occur with SARS-CoV-2.

Pathogenesis

Viral entry and interaction with target cells

SARS-CoV-2 binds to ACE two, the host target cell receptor.one Active replication and release of the virus in the lung cells atomic number 82 to non-specific symptoms such as fever, myalgia, headache, and respiratory symptoms.1 In an experimental hamster model, the virus causes transient harm to the cells in the olfactory epithelium, leading to olfactory dysfunction, which may explicate temporary loss of taste and odor commonly seen in covid-19.21 The distribution of ACE ii receptors in different tissues may explain the sites of infection and patient symptoms. For example, the ACE two receptor is constitute on the epithelium of other organs such as the intestine and endothelial cells in the kidney and claret vessels, which may explain gastrointestinal symptoms and cardiovascular complications.22 Lymphocytic endotheliitis has been observed in postmortem pathology exam of the lung, middle, kidney, and liver too every bit liver prison cell necrosis and myocardial infarction in patients who died of covid-nineteen.123 These findings indicate that the virus direct affects many organs, every bit was seen in SARS-CoV-i and influenzae.

Much remains unknown. Are the pathological changes in the respiratory tract or endothelial dysfunction the consequence 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 than, volition require further work to elucidate.

Immune response and disease spectrum (effigy 2)

Subsequently 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 well-nigh people.24 In patients who develop astringent disease, SARS-CoV-2 elicits an aberrant host allowed response.2425 For instance, postmortem histology of lung tissues of patients who died of covid-xix have confirmed the inflammatory nature of the injury, with features of bilateral diffuse alveolar impairment, hyaline-membrane germination, interstitial mononuclear inflammatory infiltrates, and desquamation consistent with acute respiratory distress syndrome (ARDS), and is similar to the lung pathology seen in astringent Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS).2627 A distinctive characteristic of covid-19 is the presence of mucus plugs with fibrinous exudate in the respiratory tract, which may explain the severity of covid-nineteen even in young adults.28 This is potentially acquired by the overproduction of pro-inflammatory cytokines that accumulate in the lungs, eventually damaging the lung parenchyma.24

Some patients also feel septic shock and multi-organ dysfunction.24 For instance, the cardiovascular system is frequently involved early in covid-xix 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; even so, further exacerbation of immune reaction and accumulation of cytokines in other organs in some patients may cause extensive tissue impairment, or a cytokine release syndrome (cytokine tempest), resulting in capillary leak, thrombus formation, and organ dysfunction.2430

Mechanisms underlying the diverse clinical outcomes

Clinical outcomes are influenced by host factors such as older age, male sexual practice, and underlying medical weather condition,ane every bit well as factors related to the virus (such every bit viral load kinetics), host-allowed response, and potential cross-reactive immune memory from previous exposure to seasonal coronaviruses (box i).

Box i

Take chances factors associated with the evolution of severe disease, admission to intensive care unit, and mortality

Underlying status

Older age
Hypertension
Cardiovascular illness
Chronic obstructive pulmonary disease
Diabetes
Obesity
Malignancy

Presentation

Higher fever (≥39°C on access)
Dyspnoea on access
College 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

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Sex-related differences in immune response accept 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 jail cell activation than men, and among male person participants T prison cell activation declined with age, which was sustained among female person patients. These findings suggest that adaptive immune response may be of import in defining the clinical outcome equally older historic period and male person sex is associated with increased risk of severe disease and mortality.

Increased levels of pro-inflammatory cytokines correlate with severe pneumonia and increased ground drinking glass opacities within the lungs.3032 In people with severe illness, increased plasma concentrations of inflammatory cytokines and biomarkers were observed compared with people with non-astringent disease.303334

Emerging evidence suggests a correlation between viral dynamics, the severity of affliction, and illness effect.7 Longitudinal characteristics of immune response show a correlation between the severity of affliction, viral load, and IFN- α, IFN-γ, and TNF-α response.34 In the same written report 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 defense force factors. This is in keeping with the pathogenesis of influenza, SARS, and MERS whereby prolonged viral shedding was also associated with severity of affliction.735

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

Tabular array 1

Therapeutics currently nether investigation

Immune response to the virus and its function in protection

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

Unanswered questions

Farther 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 empathise the determinants of good for you versus dysfunctional response and immune markers for protection and the severity of illness. Neutralising antibodies are potential correlates of protection, but other protective antibody mechanisms may exist. Similarly, the protective role of T jail cell amnesty and duration of both antibiotic and T cell responses and the correlates of protection need to be divers. In addition, nosotros need optimal testing systems and technologies to support and inform early detection and clinical direction of infection. Greater understanding is needed regarding the long term consequences following acute affliction and multisystem inflammatory disease, especially in children.

Education into practise

How would yous depict SARS-CoV-two manual routes and ways to prevent infection?

How would you lot 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 intendance modalities?
What is the window period when patients are most infectious?
Why do some patients develop severe disease while others, peculiarly 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 constructive triage of patients?
What is the protective office of T cell immunity and duration of both antibody and T prison 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

Nosotros searched PubMed from 2000 to 18 September 2020, express to publications in English language. Our search strategy used a combination of fundamental 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 Affliction Control and Prevention and World Health Organization technical documents.

Footnotes

Author contributions: MC, KK, JK, MP drafted the first and subsequent versions of the manuscript and all authors provided disquisitional feedback and contributed to the manuscript.
Competing interests The BMJ has judged that at that place are no disqualifying financial ties to commercial companies. The authors declare the post-obit 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/proclamation-competing-interests
Provenance and peer review: deputed; externally peer reviewed.

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