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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), the respiratory illness responsible for the COVID-19 pandemic. Colloquially known as simply the coronavirus, it was previously referred to by its provisional name, 2019 novel coronavirus (2019-nCoV), and has also been called human coronavirus 2019 (HCoV-19 or hCoV-19). The World Health Organization declared the outbreak a Public Health Emergency of International Concern on 30 January 2020, and a pandemic on 11 March 2020. SARS-CoV-2 is a positive-sense single-stranded RNA virus (and hence Baltimore class IV) that is contagious in humans. As described by the US National Institutes of Health, it is the successor to SARS-CoV-1, the virus that caused the 2002–2004 SARS outbreak. Taxonomically, SARS-CoV-2 is a virus of the species ''severe acute respiratory syndrome–related coronavirus'' (SARSr-CoV). It is believed to have zoonotic origins and has close genetic similarity to bat coronaviruses, suggesting it emerged from a bat-borne virus. Research is ongoing as to whether SARS-CoV-2 came directly from bats or indirectly through any intermediate hosts. 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. Epidemiological studies estimate that each infection results in an average of 2.39-3.44 new ones when no members of the community are immune and no preventive measures are taken. The virus primarily spreads between people through close contact and via respiratory droplets produced from coughs or sneezes. It mainly enters human cells by binding to the angiotensin converting enzyme 2 (ACE2).

Terminology

During the initial outbreak in Wuhan, China, various names were used for the virus; some names used by different sources included the "coronavirus" or "Wuhan coronavirus". In January 2020, the World Health Organisation recommended "2019 novel coronavirus" (2019-nCov) as the provisional name for the virus. This was in accordance with WHO's 2015 guidance against using geographical locations, animal species, or groups of people in disease and virus names. On 11 February 2020, the International Committee on Taxonomy of Viruses adopted the official name "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). To avoid confusion with the disease SARS, the WHO sometimes refers to SARS-CoV-2 as "the COVID-19 virus" in public health communications and the name HCoV-19 was included in some research articles. The general public often calls both the virus and the disease it causes, "coronavirus". U.S. President Donald Trump repeatedly referred to the virus as the "Chinese virus" in tweets, interviews, and White House press briefings, which drew some criticism that he was stigmatizing the disease with racial or nationalistic overtones.

Virology

Infection and transmission

Human-to-human transmission of SARS-CoV-2 was confirmed on 20 January 2020, during the COVID-19 pandemic. Transmission was initially assumed to occur primarily via respiratory droplets from coughs and sneezes within a range of about . Laser light scattering experiments suggest that speaking is an additional mode of transmission and a far-reaching and under-researched one, indoors, with little air flow. Other studies have suggested that the virus may be airborne as well, with aerosols potentially being able to transmit the virus. During human-to-human transmission, an average 1000 infectious SARS-CoV-2 virions are thought to initiate a new infection. Indirect contact via contaminated surfaces is another possible cause of infection. Preliminary research indicates that the virus may remain viable on plastic (polypropylene) and stainless steel (AISI 304) for up to three days, but does not survive on cardboard for more than one day or on copper for more than four hours; the virus is inactivated by soap, which destabilises its lipid bilayer. Viral RNA has also been found in stool samples and semen from infected individuals. 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 or the first week of symptoms, and declines after. A study by a team of researchers from the University of North Carolina found that the nasal cavity is seemingly the dominant initial site for infection with subsequent aspiration-mediated virus seeding into the lungs in SARS-CoV-2 pathogenesis. They found that there was an infection gradient from high in proximal towards low in distal pulmonary epithelial cultures, with a focal infection in ciliated cells and type 2 pneumocytes in the airway and alveolar regions respectively. There is some evidence of human-to-animal transmission of SARS-CoV-2, including examples in felids. Some institutions have advised those infected with SARS-CoV-2 to restrict contact with animals.

Asymptomatic transmission

On 1February 2020, the World Health Organization (WHO) indicated that "transmission from asymptomatic cases is likely not a major driver of transmission". One meta-analysis found that 17% of infections are asymptomatic, and asymptomatic individuals were 42% less likely to transmit the virus. 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. That may explain how out of 217 onboard a cruise liner that docked at Montevideo, only 24 of 128 who tested positive for viral RNA showed symptoms. Similarly, a study of ninety-four patients hospitalized in January and February 2020 estimated patients shed the greatest amount of virus two to three days before symptoms appear and that "a substantial proportion of transmission probably occurred before first symptoms in the index case".

Reinfection

There is uncertainty about reinfection and long-term immunity. It is not known how common reinfection is, but reports have indicated that it is occurring with variable severity. The first reported case of reinfection was a 33-year-old man from Hong Kong who first tested positive on 26 March 2020, was discharged on 15 April 2020 after two negative tests, and tested positive again on 15 August 2020 (142 days later), which was confirmed by whole-genome sequencing showing that the viral genomes between the episodes belong to different clades. The findings had the implications that herd immunity may not eliminate the virus if reinfection is not an uncommon occurrence and that vaccines may not be able to provide lifelong protection against the virus. Another case study described a 25-year-old man from Nevada who tested positive for SARS-CoV-2 on 18 April 2020 and on 5 June 2020 (separated by two negative tests). Since genomic analyses showed significant genetic differences between the SARS-CoV-2 variant sampled on those two dates, the case study authors determined this was a reinfection. The man's second infection was symptomatically more severe than the first infection, but the mechanisms that could account for this are not known.

Reservoir and zoonotic origin

The first known infections from SARS-CoV-2 were discovered in Wuhan, China. The original source of viral transmission to humans remains unclear, as does whether the virus became pathogenic before or after the spillover event. Because many of the early infectees were workers at the Huanan Seafood Market, it has been suggested that the virus might have originated from the market. However, other research indicates that visitors may have introduced the virus to the market, which then facilitated rapid expansion of the infections. A March 2021 WHO report on a joint WHO-China study stated that human spillover via an intermediate animal host was the most likely explanation, with direct spillover from bats next most likely. Introduction through the food supply chain and the Huanan Seafood Market was considered another possible, but less likely, explanation. A phylogenetic network analysis of 160 early coronavirus genomes sampled from December 2019 to February 2020 showed that the virus type most closely related to the bat coronavirus was most abundant in Guangdong, China, and designated type "A". The predominant type among samples from Wuhan, "B", is more distantly related to the bat coronavirus than the ancestral type "A". Research into the natural reservoir of the virus 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. Phylogenetic analysis indicates that samples taken from ''Rhinolophus sinicus'' show a resemblance of 80% to SARS-CoV-2. Phylogenetic analysis also indicates that a virus from ''Rhinolophus affinis'', collected in Yunnan province and designated RaTG13, has a 96% resemblance to SARS-CoV-2. Bats are considered the most likely natural reservoir of SARS-CoV-2, but differences between the bat coronavirus and SARS-CoV-2 suggest that humans were infected via an intermediate host. Although the role of pangolins as an intermediate host was initially posited, subsequent studies have not substantiated their contribution to the spillover. The possible intermediate host remains elusive. Nearly half of the virus's genome has a phylogenetic lineage distinct from known relatives. A study published in July 2020 suggested that pangolins are an intermediate host of SARS-CoV-2-like coronaviruses. However, additional studies indicate that pangolins are unlikely to be reservoirs or intermediate hosts for SARS-CoV-2. Isolates obtained from pangolins seized in Guangdong were only 92% identical in sequence to the SARS-CoV-2 genome, a number that is too low for the pangolin virus to be an intermediate host. In addition, pangolins are unlikely to be reservoirs for SARS-CoV-2-like viruses because they get sick from the infection, unlike true reservoirs like bats. The receptor-binding domain of the pangolin virus spike protein is highly similar to that of SARS-CoV-2, with the five critical amino acid residues in the receptor-binding motif being identical in both viruses. However, the pangolin virus turns out to bind poorly to the human ACE2 receptor. All available evidence suggests that SARS-CoV-2 has a natural animal origin and is not genetically engineered. Nevertheless, early in the pandemic, conspiracy theories spread on social media claiming that the virus was bio-engineered by China at the Wuhan Institute of Virology. While some scientists, including former CDC director Robert R. Redfield, believe it is likely that the virus may have been studied by and escaped from the Institute, the March 2021 WHO report on the joint WHO-China study stated that such an explanation is "extremely unlikely".

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, fatality rate ~34%). It is the seventh known coronavirus to infect people, after 229E, NL63, OC43, HKU1, MERS-CoV, and the original SARS-CoV. Like the SARS-related coronavirus implicated in the 2003 SARS outbreak, SARS-CoV-2 is a member of the subgenus ''Sarbecovirus'' (beta-CoV lineage B). Its RNA sequence is approximately 30,000 bases in length, relatively long for a coronavirus. SARS-CoV-2 is unique among known betacoronaviruses in its incorporation of a polybasic site cleaved by furin, a characteristic known to increase pathogenicity and transmissibility in other viruses. 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; the number of genomes increased to 42 by 30 January 2020. 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. 4,690 SARS-CoV-2 genomes sampled on six continents were publicly available. On 11 February 2020, the International Committee on Taxonomy of Viruses announced that according to existing rules that compute hierarchical relationships among coronaviruses based on five conserved sequences of nucleic acids, the differences between what was then called 2019-nCoV and the virus from the 2003 SARS outbreak were insufficient to make them separate viral species. Therefore, they identified 2019-nCoV as a virus of ''Severe acute respiratory syndrome–related coronavirus''. In July 2020, scientists reported that a more infectious SARS-CoV-2 variant with spike protein variant G614 has replaced D614 as the dominant form in the pandemic. In October 2020 scientists reported in a preprint that a variant, '' 20A.EU1'', was first observed in Spain in early summer and has become the most frequent variant in multiple European countries. They also illustrate the emergence and spread of other frequent clusters of sequences using Nextstrain. In October 2020, researchers discovered a possible overlapping gene named ''ORF3d'', in the Covid-19 virus genome. It is unknown if the protein produced by ''ORF3d'' has any function, but it provokes a strong immune response. ''ORF3d'' has been identified before, in a variant of coronavirus that infects pangolins.

Variants

There are many thousands of variants of SARS-CoV-2, which can be grouped into the much larger clades. Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR). Several notable variants of SARS-CoV-2 emerged in late 2020. * Lineage B.1.1.7 (formerly known as Variant of Concern 202012/01 (VOC 202012/01)) is believed to have emerged in the United Kingdom in September 2020. Epidemiological markers suggest that the variant is more transmissible and lethal. Among the variant's several mutations is one in the receptor-binding domain of the spike protein that changes the asparagine at position 501 to tyrosine (N501Y). This mutation may cause the virus to bind more tightly to the ACE2 receptor. It is currently spread globally. * The 501.V2 variant, which has the same N501Y mutation, arose independently in South Africa. It was detected in patient specimens collected at the beginning of October 2020 and currently spread globally. * The B.1.207 variant appeared in Nigeria. It has a mutation in the spike protein (P681H) that is also found in the VOC 202012/01 variant. P681H is located near the S1/S2 furin cleavage site. There is no evidence that the mutations increase transmissibility of the variant. * The Lineage B.1.525 first cases were detected in December 2020 in the United Kingdom and Nigeria. It is currently spread globally. * The Cluster 5 variant emerged among minks and mink farmers in Denmark. It has a set of mutations that have not been observed in other variants, including four amino acid changes in the spike protein. The variant moderately resists neutralizing antibodies. After strict quarantines, a ban on mink farming, and a mink euthanasia campaign, it is believed to have been eradicated. * Lineage P.1 first detected in Manaus, Brazil and already spread globally, the preprint works showed the variant to be more transmissible and have higher rate of deaths than B.1.1.28 and B.1.195 lineages.

Structural biology

Each SARS-CoV-2 virion is 50–200 nanometres in diameter. 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. The spike protein, which has been imaged at the atomic level using cryogenic electron microscopy, is the protein responsible for allowing the virus to attach to and fuse with the membrane of a host cell; specifically, its S1 subunit catalyzes attachment, the S2 subunit fusion. 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. 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. Studies have shown that SARS-CoV-2 has a higher affinity to human ACE2 than the original SARS virus. SARS-CoV-2 may also use basigin to assist in cell entry. Initial spike protein priming by transmembrane protease, serine 2 (TMPRSS2) is essential for entry of SARS-CoV-2. The host protein neuropilin 1 (NRP1) may aid the virus in host cell entry using ACE2. 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 in the S2 subunit, and the host receptor ACE2. After fusion, an endosome forms around the virion, separating it from the rest of the host cell. The virion escapes when the pH of the endosome drops or when cathepsin, a host cysteine protease, cleaves it. The virion then releases RNA into the cell and forces the cell to produce and disseminate copies of the virus, which infect more cells. SARS-CoV-2 produces at least three virulence factors that promote shedding of new virions from host cells and inhibit immune response. Whether they include downregulation of ACE2, as seen in similar coronaviruses, remains under investigation (as of May 2020).

Epidemiology

Based on the low variability exhibited among known SARS-CoV-2 genomic sequences, health authorities likely detected the virus within weeks of its emergence among the human population in late 2019. The earliest case of infection currently known is dated to 1 December 2019, although an earlier case could have occurred on 17 November 2019. The virus subsequently spread to all provinces of China and to more than 150 other countries across the world. Human-to-human transmission of the virus has been confirmed in all these regions. On 30 January 2020, SARS-CoV-2 was designated a Public Health Emergency of International Concern by the WHO, and on 11 March 2020 the WHO declared it a pandemic. Retrospective tests collected within the Chinese surveillance system revealed no clear indication of substantial unrecognized circulation of SARS-CoV-2 in Wuhan during the latter part of 2019. The basic reproduction number ($R_0$) of the virus has been estimated to be around 5.7. This means each infection from the virus is expected to result in 5.7 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. Many forms of preventive efforts may be employed in specific circumstances to reduce the propagation of the virus. There have been about 96,000 confirmed cases of infection in mainland China. While the proportion of infections that result in confirmed cases or progress to diagnosable disease remains unclear, one mathematical model estimated that 75,815 people were infected on 25 January 2020 in Wuhan alone, at a time when the number of confirmed cases worldwide was only 2,015. Before 24 February 2020, over 95% of all deaths from COVID-19 worldwide had occurred in Hubei province, where Wuhan is located. As of , the percentage had decreased to . As of , there have been total confirmed cases of SARS-CoV-2 infection in the ongoing pandemic. The total number of deaths attributed to the virus is . Many recoveries from both confirmed and untested infections go unreported, since some countries do not collect this data, but at least people have recovered from confirmed infections.

References