sars-related coronavirus sars-related coronavirus severe acute respiratory syndrome–related coronavirus (sarsr-cov or sars-cov) is a species of virus consisting of many known strains phylogenetically related to severe acute respiratory syndrome coronavirus 1 (sars-cov-1) that have been shown to possess the capability to infect humans, bats, and certain other mammals. these enveloped, positive-sense single-stranded rna viruses enter host cells by binding to the angiotensin-converting enzyme 2 (ace2) receptor. the sarsr-cov species is a member of the genus betacoronavirus and of the subgenus sarbecovirus (sars betacoronavirus). this article is about a species of coronavirus comprising multiple strains. for the strain that causes sars, see sars-cov-1. for the strain that causes covid-19, see sars-cov-2. severe acute respiratory syndrome–related coronavirus transmission electron micrograph of sars-related coronaviruses emerging from host cells cultured in the lab virus classification (unranked): virus realm: riboviria kingdom: orthornavirae phylum: pisuviricota class: pisoniviricetes order: nidovirales family: coronaviridae genus: betacoronavirus subgenus: sarbecovirus species: severe acute respiratory syndrome–related coronavirus strains sars-cov-1 sars-cov-2 bat sars-like coronavirus wiv1 bat coronavirus ratg13 numerous other bat-hosted strains synonyms sars coronavirus sars-related coronavirus severe acute respiratory syndrome coronavirus two strains of the virus have caused outbreaks of severe respiratory diseases in humans: severe acute respiratory syndrome coronavirus 1 (sars-cov or sars-cov-1), which caused the 2002–2004 outbreak of severe acute respiratory syndrome (sars), and severe acute respiratory syndrome coronavirus 2 (sars-cov-2), which is causing the ongoing pandemic of covid-19. there are hundreds of other strains of sarsr-cov, which are only known to infect non-human species: bats are a major reservoir of many strains of sarsr-cov; several strains have been identified in himalayan palm civets, which were likely ancestors of sars-cov-1. the sars-related coronavirus was one of several viruses identified by the world health organization (who) in 2016 as a likely cause of a future epidemic in a new plan developed after the ebola epidemic for urgent research and development before and during an epidemic towards diagnostic tests, vaccines and medicines. this prediction came to pass with the covid-19 pandemic. classification sars-related coronavirus is a member of the genus betacoronavirus (group 2) and monotypic of the subgenus sarbecovirus (subgroup b). sarbecoviruses, unlike embecoviruses or alphacoronaviruses, have only one papain-like proteinase (plpro) instead of two in the open reading frame orf1ab. sarsr-cov was determined to be an early split-off from the betacoronaviruses based on a set of conserved domains that it shares with the group. bats serve as the main host reservoir species for the sars-related coronaviruses like sars-cov-1 and sars-cov-2. the virus has coevolved in the bat host reservoir over a long period of time. only recently have strains of sars-related coronavirus been observed to have evolved into having been able to make the cross-species jump from bats to humans, as in the case of the strains sars-cov-1 and sars-cov-2. both of these strains descended from a single ancestor but made the cross-species jump into humans separately. sars-cov-2 is not a direct descendant of sars-cov-1. genome genome organization and viral proteins of sars-cov the sars-related coronavirus is an enveloped, positive-sense, single-stranded rna virus. its genome is about 30 kb, which is one of the largest among rna viruses. the virus has 14 open reading frames which overlap in some cases. the genome has the usual 5′ methylated cap and a 3′ polyadenylated tail. there are 265 nucleotides in the 5'utr and 342 nucleotides in the 3'utr. the 5' methylated cap and 3' polyadenylated tail allows the positive-sense rna genome to be directly translated by the host cell's ribosome on viral entry. sarsr-cov is similar to other coronaviruses in that its genome expression starts with translation by the host cell's ribosomes of its initial two large overlapping open reading frames (orfs), 1a and 1b, both of which produce polyproteins. function of sarsr-cov genome proteins proteinfunction orf1abp0c6x7 replicase/transcriptase polyprotein (pp1ab) (nonstructural proteins) orf2p59594 spike (s) protein, virus binding and entry (structural protein) orf3ap59632interacts with s, e, m structural proteins; ion channel activity; upregulates cytokines and chemokines such as il-8 and rantes; upregulates nf-κb and jnk; induces apoptosis and cell cycle arrest, via caspase 8 and -9, and by bax, p53, and p38 map kinase orf3bp59633upregulates cytokines and chemokines by runx1b; inhibits type i ifn production and signaling; induces apoptosis and cell cycle arrest; orf3cp0dtg1unknown; first identified in sars-cov-2 but also present in sars-cov orf3dp0dtg0novel gene in sars-cov-2, of unknown function orf4p59637 envelope (e) protein, virus assembly and budding (structural protein) orf5p59596 membrane (m) protein, virus assembly and budding (structural protein) orf6p59634enhances cellular dna synthesis; inhibits type i ifn production and signaling orf7ap59635inhibits cellular protein synthesis; induces inflammatory response by nf-kappab and il-8 promotor; upregulate chemokines such as il-8 and rantes; upregulates jnk, p38 map kinase; induces apoptosis and cell cycle arrest orf7bq7tfa1unknown orf8aq7tfa0induces apoptosis through mitochondria pathway orf8bq80h93enhances cellular dna synthesis, also known as x5. orf9ap59595 nucleocapsid (n) protein, viral rna packaging (structural protein) orf9bp59636induces apoptosis orf9cq7tlc7also known as orf14; function unknown and may not be protein-coding orf10a0a663dja2novel gene in sars-cov-2, of unknown function; may not be protein-coding uniprot identifiers shown for sars-cov proteins unless they are specific to sars-cov-2 the functions of several of the viral proteins are known. orfs 1a and 1b encode the replicase/transcriptase polyprotein, and later orfs 2, 4, 5, and 9a encode, respectively, the four major structural proteins: spike (s), envelope (e), membrane (m), and nucleocapsid (n). the later orfs also encode for eight unique proteins (orf3a to orf9b), known as the accessory proteins, many with no known homologues. the different functions of the accessory proteins are not well understood. sars coronaviruses have been genetically engineered in several laboratories. phylogenetics phylogenetic analysis showed that the evolutionary branch composed of bat coronavirus btky72 and bm48-31 was the base group of sars–related covs evolutionary tree, which separated from other sars–related covs earlier than sars-cov-1 and sars-cov-2. sarsr‑cov bat cov btky72 bat cov bm48-31 sars-cov-1 related coronavirus sars-cov-2 related coronavirus sars-cov-1 related a phylogenetic tree based on whole-genome sequences of sars-cov-1 and related coronaviruses is: sars‑cov‑1 related coronavirus 16bo133, 86.3% to sars-cov-1, rhinolophus ferrumequinum, north jeolla, south korea jtmc15, 86.4% to sars-cov-1, rhinolophus ferrumequinum, tonghua, jilin bat sars cov rf1, 87.8% to sars-cov-1, rhinolophus ferrumequinum, yichang, hubei btcov hku3, 87.9% to sars-cov-1, rhinolophus sinicus, hong kong and guangdong lyra11, 90.9% to sars-cov-1, rhinolophus affinis, baoshan, yunnan bat sars-cov/rp3, 92.6% to sars-cov-1, rhinolophus pearsoni, nanning, guangxi bat sl-cov ynlf_31c, 93.5% to sars-cov-1, rhinolophus ferrumequinum, lufeng, yunnan bat sl-cov ynlf_34c, 93.5% to sars-cov-1, rhinolophus ferrumequinum, lufeng, yunnan shc014-cov, 95.4% to sars-cov-1, rhinolophus sinicus, kunming, yunnan wiv1, 95.6% to sars-cov-1, rhinolophus sinicus, kunming, yunnan wiv16, 96.0% to sars-cov-1, rhinolophus sinicus kunming, yunnan civet sars-cov, 99.8% to sars-cov-1, paguma larvata, market in guangdong, china sars-cov-1 sars-cov-2, 79% to sars-cov-1 sars-cov-2 related a phylogenetic tree based on whole-genome sequences of sars-cov-2 and related coronaviruses is: sars‑cov‑2 related coronavirus (bat) rc-o319, 81% to sars-cov-2, rhinolophus cornutus, iwate, japan bat sl-zxc21, 88% to sars-cov-2, rhinolophus pusillus, zhoushan, zhejiang bat sl-zc45, 88% to sars-cov-2, rhinolophus pusillus, zhoushan, zhejiang pangolin sarsr-cov-gx, 85.3% to sars-cov-2, manis javanica, smuggled from southeast asia pangolin sarsr-cov-gd, 90.1% to sars-cov-2, manis javanica, smuggled from southeast asia bat rshstt182, 92.6% to sars-cov-2, rhinolophus shameli, steung treng, cambodia bat rshstt200, 92.6% to sars-cov-2, rhinolophus shameli, steung treng, cambodia (bat) raccs203, 91.5% to sars-cov-2, rhinolophus acuminatus, chachoengsao, thailand (bat) rmyn02, 93.3% to sars-cov-2, rhinolophus malayanus, mengla, yunnan (bat) rpyn06, 94.4% to sars-cov-2, rhinolophus pusillus, xishuangbanna, yunnan (bat) ratg13, 96.1% to sars-cov-2, rhinolophus affinis, mojiang, yunnan (bat) banal-52, 96.8% to sars-cov-2, rhinolophus malayanus, vientiane, laos sars-cov-2 sars-cov-1, 79% to sars-cov-2 morphology illustration created at the centers for disease control and prevention (cdc), reveals ultrastructural morphology exhibited by coronaviruses; note the spikes that adorn the outer surface, which impart the look of a corona surrounding the virion. illustration of sarsr-cov virion the morphology of the sars-related coronavirus is characteristic of the coronavirus family as a whole. the viruses are large pleomorphic spherical particles with bulbous surface projections that form a corona around the particles in electron micrographs. the size of the virus particles is in the 80–90 nm range. the envelope of the virus in electron micrographs appears as a distinct pair of electron dense shells. the viral envelope consists of a lipid bilayer where the membrane (m), envelope (e) and spike (s) proteins are anchored. the spike proteins provide the virus with its bulbous surface projections, known as peplomers. the spike protein's interaction with its complement host cell receptor is central in determining the tissue tropism, infectivity, and species range of the virus. inside the envelope, there is the nucleocapsid, which is formed from multiple copies of the nucleocapsid (n) protein, which are bound to the positive-sense single-stranded (~30 kb) rna genome in a continuous beads-on-a-string type conformation. the lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host. life cycle sars-related coronavirus follows the replication strategy typical of all coronaviruses. attachment and entry coronavirus replication cycle the attachment of the sars-related coronavirus to the host cell is mediated by the spike protein and its receptor. the spike protein receptor binding domain (rbd) recognizes and attaches to the angiotensin-converting enzyme 2 (ace2) receptor. following attachment, the virus can enter the host cell by two different paths. the path the virus takes depends on the host protease available to cleave and activate the receptor-attached spike protein. the attachment of sarbecoviruses to ace2 has been shown to be an evolutionarily conserved feature, present in many species of the taxon. the first path the sars coronavirus can take to enter the host cell is by endocytosis and uptake of the virus in an endosome. the receptor-attached spike protein is then activated by the host's ph-dependent cysteine protease cathepsin l. activation of the receptor-attached spike protein causes a conformational change, and the subsequent fusion of the viral envelope with the endosomal wall. alternatively, the virus can enter the host cell directly by proteolytic cleavage of the receptor-attached spike protein by the host's tmprss2 or tmprss11d serine proteases at the cell surface. in the sars coronavirus, the activation of the c-terminal part of the spike protein triggers the fusion of the viral envelope with the host cell membrane by inducing conformational changes which are not fully understood. genome translation function of coronavirus nonstructural proteins (nsps) proteinfunction nsp1promotes host mrna degradation, blocks host translation; blocks innate immune response nsp2binds to prohibitin proteins; unknown function nsp3multidoman transmembrane protein; interacts with n protein; promotes cytokine expression; plpro domain cleaves polyprotein pp1ab and blocks host's innate immune response; other domains unknown functions nsp4transmembrane scaffold protein; allows proper structure for double membrane vesicles (dmvs) nsp53clpro cleaves polyprotein pp1ab nsp6transmembrane scaffold protein; unknown function nsp7forms hexadecameric complex with nsp8; processivity clamp for rdrp (nsp12) nsp8forms hexadecameric complex with nsp7; processivity clamp for rdrp (nsp12); acts as a primase nsp9rna-binding protein (rbp) nsp10nsp16 and nsp14 cofactor; forms heterodimer with both; stimulates 2-o-mt (nsp16) and exon (nsp14) activity nsp11unknown function nsp12rna-dependent rna polymerase (rdrp) nsp13rna helicase, 5′ triphosphatase nsp14n7 methyltransferase, 3′-5′ exoribonuclease (exon); n7 mtase adds 5′ cap, exon proofreads genome nsp15endoribonuclease (nendou) nsp162′-o-methyltransferase (2-o-mt); protects viral rna from mda5 after fusion the nucleocapsid passes into the cytoplasm, where the viral genome is released. the genome acts as a messenger rna, and the cell's ribosome translates two-thirds of the genome, which corresponds to the open reading frame orf1a and orf1b, into two large overlapping polyproteins, pp1a and pp1ab. the larger polyprotein pp1ab is a result of a -1 ribosomal frameshift caused by a slippery sequence (uuuaaac) and a downstream rna pseudoknot at the end of open reading frame orf1a. the ribosomal frameshift allows for the continuous translation of orf1a followed by orf1b. the polyproteins contain their own proteases, plpro and 3clpro, which cleave the polyproteins at different specific sites. the cleavage of polyprotein pp1ab yields 16 nonstructural proteins (nsp1 to nsp16). product proteins include various replication proteins such as rna-dependent rna polymerase (rdrp), rna helicase, and exoribonuclease (exon). the two sars-cov-2 proteases (plpro and 3clpro) also interfere with the immune system response to the viral infection by cleaving three immune system proteins. plpro cleaves irf3 and 3clpro cleaves both nlrp12 and tab1. "direct cleavage of irf3 by nsp3 could explain the blunted type-i ifn response seen during sars-cov-2 infections while nsp5 mediated cleavage of nlrp12 and tab1 point to a molecular mechanism for enhanced production of il-6 and inflammatory response observed in covid-19 patients."