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.
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.[17] 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.[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 the
positive-sense RNA genome to be directly
translated by the host cell's
ribosome on
viral 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 produce
polyproteins.[19]
Inhibits 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
Novel 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.[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), and
nucleocapsid (N).[27] 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.[26]
SARS coronaviruses have been genetically engineered in several laboratories.[28]
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.[29][3]
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:
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.[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 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.[55][56] The lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host.[57]
Life cycle
SARS-related coronavirus follows the replication strategy typical of all coronaviruses.[20][58]
Attachment and entry
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 the
angiotensin-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 host
protease available to cleave and activate the receptor-attached spike protein.[60]
The attachment of sarbecoviruses to ACE2 has been shown to be an
evolutionarily conserved feature, present in many species of the taxon.[61]
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 proteasecathepsin L. Activation of the receptor-attached spike protein causes a
conformational change, and the subsequent fusion of the viral envelope with the
endosomal wall.[60]
Alternatively, the virus can enter the host cell directly by
proteolytic cleavage of the receptor-attached spike protein by the host's
TMPRSS2 or
TMPRSS11Dserine proteases at the cell surface.[62][63] 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.[64]
Genome translation
Function of coronavirus nonstructural proteins (nsps)[65]
After fusion the nucleocapsid passes into the
cytoplasm, where the viral genome is released.[59] 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.[67] The ribosomal frameshift allows for the continuous translation of ORF1a followed by ORF1b.[68]
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).[68]
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."[69]
Replication and transcription
A number of the nonstructural replication proteins coalesce to form a
multi-protein replicase-transcriptase complex (RTC).[68] The main replicase-transcriptase protein is the
RNA-dependent RNA polymerase (RdRp). It is directly involved in the
replication and
transcription of RNA from an RNA strand. The other nonstructural proteins in the complex assist in the replication and transcription process.[65]
The protein nsp14 is a
3'-5' exoribonuclease which provides extra fidelity to the replication process. The exoribonuclease provides a
proofreading 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 the
processivity of the RNA-dependent RNA polymerase.[65] The coronaviruses require the increased fidelity and processivity during RNA synthesis because of the relatively large genome size in comparison to other RNA viruses.[70]
One of the main functions of the replicase-transcriptase complex is to transcribe the viral genome. RdRp directly mediates the
synthesis of negative-sense
subgenomic 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-sense
mRNAs.[71]
The other important function of the replicase-transcriptase complex is to replicate the viral genome. RdRp directly mediates the
synthesis 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.[71]
The replicated positive-sense genomic RNA becomes the genome of the
progeny 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.[72]
Recombination
When two SARS-CoV
genomes 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 the
RNA polymerase switches from one template to another (copy choice recombination).[73] Human SARS-CoV appears to have had a complex history of
recombination between ancestral
coronaviruses that were hosted in several different animal groups.[73][74]
Assembly and release
RNA translation occurs inside the
endoplasmic reticulum. The viral structural proteins S, E and M move along the secretory pathway into the
Golgi intermediate compartment. There, the M proteins direct most protein-protein interactions required for assembly of viruses following its binding to the nucleocapsid.[75] Progeny viruses are released from the host cell by
exocytosis through secretory vesicles.[75]
^The terms SARSr-CoV and SARS-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 as SARS-CoV.
^"Virus Taxonomy: 2018 Release". International Committee on Taxonomy of Viruses (ICTV). October 2018. Retrieved 13 January 2019.
^Woo PC, Huang Y, Lau SK, Yuen KY (August 2010).
"Coronavirus genomics and bioinformatics analysis". Viruses. 2 (8): 1804–20.
doi:10.3390/v2081803.
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PMID21994708. Figure 2. Phylogenetic analysis of RNA-dependent RNA polymerases (Pol) of coronaviruses with complete genome sequences available. The tree was constructed by the neighbor-joining method and rooted using Breda virus polyprotein.
^Woo PC, Huang Y, Lau SK, Yuen KY (August 2010).
"Coronavirus genomics and bioinformatics analysis". Viruses. 2 (8): 1804–20.
doi:10.3390/v2081803.
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PMID21994708. Furthermore, subsequent phylogenetic analysis using both complete genome sequence and proteomic approaches, it was concluded that SARSr-CoV is probably an early split-off from the Betacoronavirus lineage [1]; See Figure 2.
^
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^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.
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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.
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^Goldsmith CS, Tatti KM, Ksiazek TG, Rollin PE, Comer JA, Lee WW, et al. (February 2004).
"Ultrastructural characterization of SARS coronavirus". Emerging Infectious Diseases. 10 (2): 320–6.
doi:
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PMC3322934.
PMID15030705. Virions acquired an envelope by budding into the cisternae and formed mostly spherical, sometimes pleomorphic, particles that averaged 78 nm in diameter (Figure 1A).
^Masters PS (1 January 2006). The molecular biology of coronaviruses. Advances in Virus Research. Vol. 66. Academic Press. pp. 193–292.
doi:
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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:
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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:
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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:
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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).
^Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY (May 2016).
"Coronaviruses - drug discovery and therapeutic options". Nature Reviews. Drug Discovery. 15 (5): 327–47.
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PMC7097181.
PMID26868298. S is activated and cleaved into the S1 and S2 subunits by other host proteases, such as transmembrane protease serine 2 (TMPRSS2) and TMPRSS11D, which enables cell surface non-endosomal virus entry at the plasma membrane.
^
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:
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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.
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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.
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ISBN978-1-4939-2438-7.
PMC4369385.
PMID25720466. See section: Coronavirus Life Cycle – Assembly and Release
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