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Severe acute respiratory syndrome coronavirus 2

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[2][3] is the virus strain that causes coronavirus disease 2019 (COVID-19), a respiratory illness. It is colloquially known as the coronavirus, and was previously referred to by its provisional name 2019 novel coronavirus (2019-nCoV).[4][5][6] SARS-CoV-2 is a positive-sense single-stranded RNA virus.[7] It is contagious in humans, and the World Health Organization (WHO) has designated the ongoing pandemic of COVID-19 a Public Health Emergency of International Concern.[8][9][10] Because the strain was first discovered in Wuhan, China, it is sometimes referred to as the “Wuhan virus”[11][12] or “Wuhan coronavirus”.[13][14][15] Since the WHO discourages the use of names based upon locations[16][17] and to avoid confusion with the disease SARS,[18] it sometimes refers to SARS-CoV-2 as “the COVID-19 virus” in public health communications.[19] The general public frequently calls both SARS-CoV-2 and the disease it causes “coronavirus”, but scientists typically use more precise terminology.[20]

Taxonomically, SARS-CoV-2 is a strain of Severe acute respiratory syndrome-related coronavirus (SARSr-CoV).[2] It is believed to have zoonotic origins and has close genetic similarity to bat coronaviruses, suggesting it emerged from a bat-borne virus.[21][22][23] An intermediate animal reservoir such as a pangolin is also thought to be involved in its introduction to humans.[16][24] The virus shows little genetic diversity, indicating that the spillover event introducing SARS-CoV-2 to humans is likely to have occurred in late 2019.[25]

Epidemiological studies estimate each infection results in 1.4 to 3.9 new ones when no members of the community are immune and no preventive measures taken. The virus is primarily spread between people through close contact and via respiratory droplets produced from coughs or sneezes.[26][27] It mainly enters human cells by binding to the receptor angiotensin converting enzyme 2 (ACE2).[21][28][29]

Virology

Infection

Human-to-human transmission of SARS-CoV-2 has been confirmed during the 2019–20 coronavirus pandemic.[10] Transmission occurs primarily via respiratory droplets from coughs and sneezes within a range of about 1.8 metres (6 ft).[27][30] Indirect contact via contaminated surfaces is another possible cause of infection.[31] Preliminary research indicates that the virus may remain viable on plastic and steel for up to three days, but does not survive on cardboard for more than one day or on copper for more than four hours;[32] the virus is inactivated by soap, which destabilises its lipid bilayer.[33][34] Viral RNA has also been found in stool samples from infected individuals.[35]

The degree to which the virus is infectious during the incubation period is uncertain, but research has indicated that the pharynx reaches peak viral load approximately four days after infection.[36][37] On 1 February 2020, the World Health Organization (WHO) indicated that “transmission from asymptomatic cases is likely not a major driver of transmission”.[38] However, an epidemiological model of the beginning of the outbreak in China suggested that “pre-symptomatic shedding may be typical among documented infections” and that subclinical infections may have been the source of a majority of infections.[39]

There is some evidence of human-to-animal transmission of SARS-CoV-2, including examples in felids.[40][41] Some institutions have advised those infected with SARS-CoV-2 to restrict contact with animals.[42][43]

Reservoir

A horseshoe bat

Horseshoe bats are among the most likely natural reservoirs of SARS-CoV-2

The first known infections from the SARS-CoV-2 strain were discovered in Wuhan, China.[21] The original source of viral transmission to humans remains unclear, as does whether the strain became pathogenic before or after the spillover event.[25][44][45] Because many of the first individuals found to be infected by the virus were workers at the Huanan Seafood Market,[46][47] it has been suggested that the strain might have originated from the market.[45][48] However, other research indicates that visitors may have introduced the virus to the market, which then facilitated rapid expansion of the infections.[25][49]

Research into the natural reservoir of the virus strain that caused the 2002–2004 SARS outbreak has resulted in the discovery of many SARS-like bat coronaviruses, most originating in the Rhinolophus genus of horseshoe bats, and two viral nucleic acid sequences found in samples taken from Rhinolophus sinicus show a resemblance of 80% to SARS-CoV-2.[23][50][51] A third viral nucleic acid sequence from Rhinolophus affinis, collected in Yunnan province and designated RaTG13, has a 96% resemblance to SARS-CoV-2.[21][52] Bats are considered the most likely natural reservoir of SARS-CoV-2,[53][54] but differences between the bat coronavirus and SARS-CoV-2 suggest that humans were infected via an intermediate host.[48] Nearly half of the strain’s genome has a phylogenetic lineage distinct from known relatives.[55]

A metagenomic study published in 2019 previously revealed that SARS-CoV, the strain of the virus that causes SARS, was the most widely distributed coronavirus among a sample of Sunda pangolins.[56] On 7 February 2020, it was announced that researchers from Guangzhou had discovered a pangolin sample with a viral nucleic acid sequence “99% identical” to SARS-CoV-2.[57] When released, the results clarified that “the receptor-binding domain of the S protein of the newly discovered Pangolin-CoV is virtually identical to that of 2019-nCoV, with one amino acid difference.”[58] Pangolins are protected under Chinese law, but their poaching and trading for use in traditional Chinese medicine remains common.[59][60]

Microbiologists and geneticists in Texas have independently found evidence of reassortment in coronaviruses suggesting involvement of pangolins in the origin of SARS-CoV-2.[61] However, pangolin coronaviruses found to date only share at most 92% of their whole genomes with SARS-CoV-2, making them less similar than RaTG13 to SARS-CoV-2.[62] This is insufficient to prove pangolins to be the intermediate host; in comparison, the SARS virus responsible for the 2002–2004 outbreak shared 99.8% of its genome with a known civet coronavirus.[48]

Phylogenetics and taxonomy

SARS-CoV-2 belongs to the broad family of viruses known as coronaviruses. It is a positive-sense single-stranded RNA (+ssRNA) virus, with a single linear RNA segment. Other coronaviruses are capable of causing illnesses ranging from the common cold to more severe diseases such as Middle East respiratory syndrome (MERS). It is the seventh known coronavirus to infect people, after 229E, NL63, OC43, HKU1, MERS-CoV, and the original SARS-CoV.[63]

Like the SARS-related coronavirus strain implicated in the 2003 SARS outbreak, SARS-CoV-2 is a member of the subgenus Sarbecovirus (beta-CoV lineage B).[64][65] Its RNA sequence is approximately 30,000 bases in length.[7] SARS-CoV-2 is unique among known betacoronaviruses in its incorporation of a polybasic cleavage site, a characteristic known to increase pathogenicity and transmissibility in other viruses.[45][66][67]

With a sufficient number of sequenced genomes, it is possible to reconstruct a phylogenetic tree of the mutation history of a family of viruses. By 12 January 2020, five genomes of SARS-CoV-2 had been isolated from Wuhan and reported by the Chinese Center for Disease Control and Prevention (CCDC) and other institutions;[7][68] the number of genomes increased to 42 by 30 January 2020.[69] A phylogenetic analysis of those samples showed they were “highly related with at most seven mutations relative to a common ancestor”, implying that the first human infection occurred in November or December 2019.[69] As of 27 March 2020, 1,495 SARS-CoV-2 genomes sampled on six continents were publicly available.[70]

On 11 February 2020, the International Committee on Taxonomy of Viruses (ICTV) announced that according to existing rules that compute hierarchical relationships among coronaviruses on the basis of five conserved sequences of nucleic acids, the differences between what was then called 2019-nCoV and the virus strain from the 2003 SARS outbreak were insufficient to make them separate viral species. Therefore, they identified 2019-nCoV as a strain of Severe acute respiratory syndrome-related coronavirus.[2]

Structural biology

Figure of a spherical SARSr-CoV virion showing locations of structural proteins forming the viral envelope and the inner nucleocapsid

Structure of a SARSr-CoV virion

Each SARS-CoV-2 virion is approximately 50–200 nanometres in diameter.[47] Like other coronaviruses, SARS-CoV-2 has four structural proteins, known as the S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins; the N protein holds the RNA genome, and the S, E, and M proteins together create the viral envelope.[71] The spike protein, which has been imaged at the atomic level using cryogenic electron microscopy,[72][73] is the protein responsible for allowing the virus to attach to and fuse with the membrane of a host cell.[71]

SARS-CoV-2 spike homotrimer focusing upon one protein subunit with an ACE2 binding domain highlighted

SARS-CoV-2 spike homotrimer with one protein subunit highlighted; the ACE2 binding domain is in magenta

Protein modeling experiments on the spike protein of the virus soon suggested that SARS-CoV-2 has sufficient affinity to the receptor angiotensin converting enzyme 2 (ACE2) on human cells to use them as a mechanism of cell entry.[74] By 22 January 2020, a group in China working with the full virus genome and a group in the United States using reverse genetics methods independently and experimentally demonstrated that ACE2 could act as the receptor for SARS-CoV-2.[21][75][28][76] Studies have shown that SARS-CoV-2 has a higher affinity to human ACE2 than the original SARS virus strain.[72][77] SARS-CoV-2 may also use basigin to assist in cell entry.[78]

SARS-CoV-2 emerging from a human cell
SARS-CoV-2 virions emerging from a human cell
Digitally colourised scanning electron micrographs of SARS-CoV-2 virions (yellow) emerging from human cells cultured in a laboratory

Initial spike protein priming by transmembrane protease, serine 2 (TMPRSS2) is essential for entry of SARS-CoV-2.[29] After a SARS-CoV-2 virion attaches to a target cell, the cell’s protease TMPRSS2 cuts open the spike protein of the virus, exposing a fusion peptide. The virion then releases RNA into the cell, forcing the cell to produce copies of the virus that are disseminated to infect more cells.[79][better source needed]

SARS-CoV-2 produces at least three virulence factors that promote shedding of new virions from host cells and inhibit immune response.[71]

Epidemiology

Micrograph of SARS-CoV-2 virus particles isolated from a patient

Transmission electron micrograph of SARS-CoV-2 virions (red) isolated from a patient during the 2019–20 coronavirus pandemic

Based on the low variability exhibited among known SARS-CoV-2 genomic sequences, the strain is thought to have been detected by health authorities within weeks of its emergence among the human population in late 2019.[25][80] The earliest case of infection currently known is thought to have been found on 17 November 2019.[81] The virus subsequently spread to all provinces of China and to more than 150 other countries in Asia, Europe, North America, South America, Africa, and Oceania.[82] Human-to-human transmission of the virus has been confirmed in all of these regions.[83] On 30 January 2020, SARS-CoV-2 was designated a Public Health Emergency of International Concern by the WHO,[9][84] and on 11 March 2020 the WHO declared it a pandemic.[8][85]

The basic reproduction number (

R0[86][87] This means that each infection from the virus is expected to result in 1.4 to 3.9 new infections when no members of the community are immune and no preventive measures are taken. The reproduction number may be higher in densely populated conditions such as those found on cruise ships.[88] Many forms of preventive efforts may be employed in specific circumstances in order to reduce the propagation of the virus.

There have been about 82,000 confirmed cases of infection in mainland China.[82] While the proportion of infections that result in confirmed cases or progress to diagnosable disease remains unclear,[89] one mathematical model estimated that on 25 January 75,815 people were infected in Wuhan alone, at a time when the number of confirmed cases worldwide was only 2,015.[90][91] Before 24 February, over 95% of all deaths from COVID-19 worldwide had occurred in Hubei province, where Wuhan is located.[92][93] As of 15 April 2020, the percentage had decreased to 2.5%.[82]

As of 15 April 2020, there have been 1,981,239 total confirmed cases of SARS-CoV-2 infection in the ongoing pandemic.[82] The total number of deaths attributed to the virus is 126,681.[82] Many recoveries from confirmed infections go unreported, but at least 486,622 people have recovered from confirmed infections.[82]

Further reading

  • “Coronavirus Disease 2019 (COVID-19)”. Centers for Disease Control and Prevention (CDC).
  • “Coronavirus disease (COVID-19) Pandemic”. World Health Organization (WHO).
  • “SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) Sequences”. National Center for Biotechnology Information (NCBI).
  • “COVID-19 Resource Centre”. The Lancet.
  • “Coronavirus (Covid-19)”. The New England Journal of Medicine.
  • “Covid-19: Novel Coronavirus Outbreak”. Wiley.
  • “SARS-CoV-2”. Virus Pathogen Database and Analysis Resource.
  • “SARS-CoV-2 related protein structures”. Protein Data Bank.


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