This article is about a species of coronavirus comprising multiple strains. For the strain that causes SARS, seeSARS-CoV-1. For the strain that causes COVID-19, seeSARS-CoV-2.
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 thebat host reservoir over a long period of time.[17] Only recently have strains of SARS-related coronavirus been observed to have evolved into having been able to make thecross-species jump from bats to humans, as in the case of the strainsSARS-CoV-1 andSARS-CoV-2.[18][8] 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.[3]
The 5' methylated cap and 3' polyadenylated tail allows thepositive-sense RNA genome to be directlytranslated by the host cell'sribosome onviral entry.[21] 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 producepolyproteins.[19]
Novel gene in SARS-CoV-2, of unknown function; may not be protein-coding
UniProt identifiers shown forSARS-CoV proteins unless they are specific to SARS-CoV-2
The functions of several of the viral proteins are known.[26] 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), andnucleocapsid (N).[27] The later ORFs also encode for eight unique proteins (orf3a to orf9b), known as theaccessory proteins, many with no known homologues. The different functions of the accessory proteins are not well understood.[26]
SARS coronaviruses have been genetically engineered in several laboratories.[28]
Phylogenetic tree of SARS-CoV-2 and closely related betacoronaviruses (left) and their geographic context (right)
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.[29][3]
Illustration created at theCenters for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses; note thespikes that adorn the outer surface, which impart the look of a corona surrounding thevirion.[49]Illustration of SARSr-CoVvirion
The morphology of the SARS-related coronavirus is characteristic of the coronavirus family as a whole. The viruses are largepleomorphic spherical particles with bulbous surface projections that form a corona around the particles in electron micrographs.[50] 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.[51]
Inside the envelope, there is thenucleocapsid, which is formed from multiple copies of thenucleocapsid (N) protein, which are bound to the positive-sense single-stranded (~30kb) RNA genome in a continuousbeads-on-a-string type conformation.[55][56] The lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host.[57]
The attachment of the SARS-related coronavirus to the host cell is mediated by the spike protein and its receptor.[59] The spike protein receptor binding domain (RBD) recognizes and attaches to theangiotensin-converting enzyme 2 (ACE2) receptor.[8] Following attachment, the virus can enter the host cell by two different paths. The path the virus takes depends on the hostprotease available to cleave and activate the receptor-attached spike protein.[60] A notable difference between SARS-CoV-1 and SARS-CoV-2, is that SARS-CoV-2 is pre-cleaved due to its furin cleavage site.[61]
The attachment of sarbecoviruses to ACE2 has been shown to be anevolutionarily conserved feature, present in many (but not all) species of the taxon with ACE2 using representatives in Africa, Asia, and Europe.[62]
The first path the SARS coronavirus can take to enter the host cell is byendocytosis and uptake of the virus in anendosome. The receptor-attached spike protein is then activated by the host's pH-dependentcysteine proteasecathepsin L. Activation of the receptor-attached spike protein causes aconformational change, and the subsequent fusion of the viral envelope with theendosomal wall.[60]
Alternatively, the virus can enter the host cell directly byproteolytic cleavage of the receptor-attached spike protein by the host'sTMPRSS2 orTMPRSS11Dserine proteases at the cell surface.[63][64] In the SARS coronavirus, the activation of theC-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.[65]
After fusion the nucleocapsid passes into thecytoplasm, where the viral genome is released.[59] The genomeacts as a messenger RNA, and the cell's ribosometranslates two-thirds of the genome, which corresponds to the open reading frameORF1a andORF1b, into two large overlapping polyproteins, pp1a and pp1ab.
The larger polyprotein pp1ab is a result of a-1 ribosomal frameshift caused by aslippery sequence (UUUAAAC) and a downstreamRNA pseudoknot at the end of open reading frame ORF1a.[68] The ribosomal frameshift allows for the continuous translation of ORF1a followed by ORF1b.[69]
The polyproteins contain their ownproteases,PLpro and3CLpro, 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 asRNA-dependent RNA polymerase (RdRp),RNA helicase, andexoribonuclease (ExoN).[69]
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 cleavesIRF3 and 3CLpro cleaves bothNLRP12 andTAB1. "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."[70]
A number of the nonstructural replication proteins coalesce to form amulti-protein replicase-transcriptase complex (RTC).[69] The main replicase-transcriptase protein is theRNA-dependent RNA polymerase (RdRp). It is directly involved in thereplication andtranscription of RNA from an RNA strand. The other nonstructural proteins in the complex assist in the replication and transcription process.[66]
The protein nsp14 is a3'-5' exoribonuclease which provides extra fidelity to the replication process. The exoribonuclease provides aproofreading function to the complex which the RNA-dependent RNA polymerase lacks. Similarly, proteins nsp7 and nsp8 form a hexadecameric sliding clamp as part of the complex which greatly increases theprocessivity of the RNA-dependent RNA polymerase.[66] The coronaviruses require the increased fidelity and processivity during RNA synthesis because of the relatively large genome size in comparison to other RNA viruses.[71]
One of the main functions of the replicase-transcriptase complex is to transcribe the viral genome. RdRp directly mediates thesynthesis of negative-sensesubgenomic RNA molecules from the positive-sense genomic RNA. This is followed by the transcription of these negative-sense subgenomic RNA molecules to their corresponding positive-sensemRNAs.[72]
The other important function of the replicase-transcriptase complex is to replicate the viral genome. RdRp directly mediates thesynthesis of negative-sense genomic RNA from the positive-sense genomic RNA. This is followed by the replication of positive-sense genomic RNA from the negative-sense genomic RNA.[72] SARS-CoV replication and transcription mainly occurs in virus-induced double-membrane vesicles (DMVs) made from altered hostendoplasmic reticulum.[73]
The replicated positive-sense genomic RNA becomes the genome of theprogeny viruses. The various smaller mRNAs are transcripts from the last third of the virus genome which follows the reading frames ORF1a and ORF1b. These mRNAs are translated into the four structural proteins (S, E, M, and N) that will become part of the progeny virus particles and also eight other accessory proteins (orf3 to orf9b) which assist the virus.[74]
When two SARS-CoVgenomes are present in a host cell, they may interact with each other to form recombinant genomes that can be transmitted to progeny viruses. Recombination likely occurs during genome replication when theRNA polymerase switches from one template to another (copy choice recombination).[75] Human SARS-CoV appears to have had a complex history ofrecombination between ancestralcoronaviruses that were hosted in several different animal groups.[75][76]
RNA translation occurs inside theendoplasmic reticulum. The viral structural proteins S, E and M move along the secretory pathway into theGolgi intermediate compartment. There, the M proteins direct most protein-protein interactions required for assembly of viruses following its binding to the nucleocapsid.[77] Progeny viruses are released from the host cell byexocytosis through secretory vesicles.[77]
^The termsSARSr-CoV andSARS-CoV are sometimes used interchangeably, especially prior to the discovery of SARS-CoV-2. This may cause confusion when some publications refer to SARS-CoV-1 asSARS-CoV.
^abXing‐Yi Ge; Ben Hu; Zheng‐Li Shi (2015). "BAT CORONAVIRUSES". In Lin-Fa Wang; Christopher Cowled (eds.).Bats and Viruses: A New Frontier of Emerging Infectious Diseases (First ed.). John Wiley & Sons. pp. 127–155.doi:10.1002/9781118818824.ch5.
^Masters PS (1 January 2006).The molecular biology of coronaviruses. Advances in Virus Research. Vol. 66. Academic Press. pp. 193–292.doi:10.1016/S0065-3527(06)66005-3.ISBN9780120398690.PMC7112330.PMID16877062.Nevertheless, the interaction between S protein and receptor remains the principal, if not sole, determinant of coronavirus host species range and tissue tropism.
^Fehr AR, Perlman S (2015). "Coronaviruses: An Overview of Their Replication and Pathogenesis". In Maier HJ, Bickerton E, Britton P (eds.).Coronaviruses. Methods in Molecular Biology. Vol. 1282. Springer. pp. 1–23.doi:10.1007/978-1-4939-2438-7_1.ISBN978-1-4939-2438-7.PMC4369385.PMID25720466.See section: Virion Structure.
^abFehr AR, Perlman S (2015). "Coronaviruses: An Overview of Their Replication and Pathogenesis". In Maier HJ, Bickerton E, Britton P (eds.).Coronaviruses. Methods in Molecular Biology. Vol. 1282. Springer. pp. 1–23.doi:10.1007/978-1-4939-2438-7_1.ISBN978-1-4939-2438-7.PMC4369385.PMID25720466.See section: Coronavirus Life Cycle – Attachment and Entry
^Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S (January 2014)."TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein".Journal of Virology.88 (2):1293–307.doi:10.1128/JVI.02202-13.PMC3911672.PMID24227843.The SARS-CoV can hijack two cellular proteolytic systems to ensure the adequate processing of its S protein. Cleavage of SARS-S can be facilitated by cathepsin L, a pH-dependent endo-/lysosomal host cell protease, upon uptake of virions into target cell endosomes (25). Alternatively, the type II transmembrane serine proteases (TTSPs) TMPRSS2 and HAT can activate SARS-S, presumably by cleavage of SARS-S at or close to the cell surface, and activation of SARS-S by TMPRSS2 allows for cathepsin L-independent cellular entry (26,–28).
^abcFehr AR, Perlman S (2015). "Coronaviruses: An Overview of Their Replication and Pathogenesis". In Maier HJ, Bickerton E, Britton P (eds.).Coronaviruses. Methods in Molecular Biology. Vol. 1282. Springer. pp. 1–23.doi:10.1007/978-1-4939-2438-7_1.ISBN978-1-4939-2438-7.PMC4369385.PMID25720466.See Table 2.
^abcFehr AR, Perlman S (2015). "Coronaviruses: An Overview of Their Replication and Pathogenesis". In Maier HJ, Bickerton E, Britton P (eds.).Coronaviruses. Methods in Molecular Biology. Vol. 1282. Springer. pp. 1–23.doi:10.1007/978-1-4939-2438-7_1.ISBN978-1-4939-2438-7.PMC4369385.PMID25720466.See section: Replicase Protein Expression
^abFehr AR, Perlman S (2015). "Coronaviruses: An Overview of Their Replication and Pathogenesis". In Maier HJ, Bickerton E, Britton P (eds.).Coronaviruses. Methods in Molecular Biology. Vol. 1282. Springer. pp. 1–23.doi:10.1007/978-1-4939-2438-7_1.ISBN978-1-4939-2438-7.PMC4369385.PMID25720466.See section: Corona Life Cycle – Replication and Transcription
^Fehr AR, Perlman S (2015). "Coronaviruses: An Overview of Their Replication and Pathogenesis". In Maier HJ, Bickerton E, Britton P (eds.).Coronaviruses. Methods in Molecular Biology. Vol. 1282. Springer. pp. 1–23.doi:10.1007/978-1-4939-2438-7_1.ISBN978-1-4939-2438-7.PMC4369385.PMID25720466.See Figure 1.
^abZhang XW, Yap YL, Danchin A. Testing the hypothesis of a recombinant origin of the SARS-associated coronavirus. Arch Virol. 2005 Jan;150(1):1-20. Epub 2004 Oct 11. PMID 15480857
^Stanhope MJ, Brown JR, Amrine-Madsen H. Evidence from the evolutionary analysis of nucleotide sequences for a recombinant history of SARS-CoV. Infect Genet Evol. 2004 Mar;4(1):15-9. PMID 15019585
^abFehr AR, Perlman S (2015). "Coronaviruses: An Overview of Their Replication and Pathogenesis". In Maier HJ, Bickerton E, Britton P (eds.).Coronaviruses. Methods in Molecular Biology. Vol. 1282. Springer. pp. 1–23.doi:10.1007/978-1-4939-2438-7_1.ISBN978-1-4939-2438-7.PMC4369385.PMID25720466.See section: Coronavirus Life Cycle – Assembly and Release
Enjuanes L, Sola I, Zúñiga S, Almazán F (2008). "Coronavirus Replication and Interaction with Host". In Mettenleiter TC, Sobrino F (eds.).Animal Viruses: Molecular Biology. Caister Academic Press.ISBN978-1-904455-22-6.
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