|Severe acute respiratory syndrome-related coronavirus|
|Transmission electron micrograph of SARS-related coronaviruses emerging from host cells cultured in the lab|
Severe acute respiratory syndrome-related coronavirus
Severe acute respiratory syndrome-related coronavirus (SARSr-CoV)[note 1] is a species of coronavirus that infects humans, bats and certain other mammals. It is an enveloped positive-sense single-stranded RNA virus that enters its host cell by binding to the ACE2 receptor. It is a member of the genus Betacoronavirus and subgenus Sarbecoronavirus.
Two strains of the virus have caused outbreaks of severe respiratory diseases in humans: SARS-CoV (or SARS-CoV-1), which caused the 2002-2004 outbreak of severe acute respiratory syndrome (SARS), and SARS-CoV-2, which is causing the 2019–20 pandemic of coronavirus disease 2019 (COVID-19). There are hundreds of other strains of SARSr-CoV, all of which are only known to infect non-human species: bats are a major reservoir of many strains of SARS-related coronaviruses, and several strains have been identified in palm civets, which were likely ancestors of SARS-CoV.
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. The prediction came to pass with the 2019–20 coronavirus pandemic.
SARS-related coronavirus is a member of the genus Betacoronavirus (group 2) and subgenus Sarbecovirus (subgroup B). Sarbecoviruses, unlike embecoviruses or alphacoronaviruses, only have one papain-like proteinase (PLpro) instead of two in the open reading frame ORF1. 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 for the SARS-related coronavirus. The virus has coevolved in the bat host reservoir over a long period of time. Only recently have strains of SARS-related coronavirus evolved and made the cross-species jump from bats to humans, as in the case of the strains SARS-CoV and SARS-CoV-2. Both 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. On 17 March 2020, scientists reported that the novel SARS-CoV-2 virus originated naturally, and not otherwise.
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 a 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 SARS-CoV |
genome proteins (orf1a to orf9b)
|Replicase/transcriptase polyprotein (pp1ab) |
|orf2||Spike (S) protein, virus binding and entry |
|orf3a||Interacts 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
|orf3b||Upregulates cytokines and chemokines by RUNX1b; |
Inhibits Type I IFN production and signaling;
Induces apoptosis and cell cycle arrest;
|orf4||Envelope (E) protein, virus assembly and budding |
|orf5||Membrane (M) protein, virus assembly and budding |
|orf6||Enhances cellular DNA synthesis; |
Inhibits Type I IFN production and signaling
|orf7a||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
|orf8a||Induces apoptosis through mitochondria pathway|
|orf8b||Enhances cellular DNA synthesis|
|orf9a||Nucleocapsid (N) protein, viral RNA packaging |
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, envelope, membrane, and nucleocapsid. 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.
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. 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.
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 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.
|Function of coronavirus |
nonstructural proteins (nsps)
|nsp1||Promotes host mRNA degradation, blocks host translation; |
blocks innate immune response
|nsp2||Binds to prohibitin proteins; |
|nsp3||Multidoman 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|
|nsp4||Transmembrane scaffold protein; |
allows proper structure for double membrane vesicles (DMVs)
|nsp5||3CLPro cleaves polyprotein pp1ab|
|nsp6||Transmembrane scaffold protein; |
|nsp7||Forms hexadecameric complex with nsp8; processivity clamp for RdRp (nsp12)|
|nsp8||Forms hexadecameric complex with nsp7; processivity clamp for RdRp (nsp12); acts as a primase|
|nsp9||RNA binding protein (RBP)|
|nsp10||nsp16 and nsp14 cofactor; forms heterodimer with both; stimulates 2-O-MT (nsp16) and ExoN (nsp14) activity|
|nsp12||RNA-dependent RNA polymerase (RdRp)|
|nsp13||RNA helicase, 5′ triphosphatase|
|nsp14||N7 Mehtyltransferase, 3′-5′ exoribonuclease (ExoN); N7 MTase adds 5′ cap, ExoN proofreads genome|
|nsp16||2′-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).
A number of the nonstructural replication proteins coalesce to form a multi-protein replicase-transcriptase complex (RTC). 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.
The protein nsp15 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. The coronaviruses require the increased fidelity and processivity during RNA synthesis because of the relatively large genome size in comparison to other RNA viruses.
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.
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.
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.
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.
Most notably, horseshoe bats were found to be the reservoir of SARS-like CoVs, while palm civet cats are considered to be the intermediate host for SARS-CoVs [43,44,45].
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.
See Figure 1.
See Figure 1.
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 ; See Figure 2.
See Figure 2.
Betacoronaviruses-b ancestors, meaning SARSr-CoVs ancestors, could have been historically hosted by the common ancestor of the Rhinolophidae and Hipposideridae and could have later evolved independently in the lineages leading towards Rhinolophidae and Hipposideridae betacoronaviruses.
The SARS-CoV genome is ∼29.7 kb long and contains 14 open reading frames (ORFs) flanked by 5′ and 3′-untranslated regions of 265 and 342 nucleotides, respectively (Figure 1).
See Table 1.
See Table 1.
See Figure 1.
Virions acquired an envelope by budding into the cisternae and formed mostly spherical, sometimes pleomorphic, particles that averaged 78 nm in diameter (Figure 1A).
Particle diameters ranged from 50 to 150 nm, excluding the spikes, with mean particle diameters of 82 to 94 nm; Also See Figure 1 for double shell.
Nevertheless, the interaction between S protein and receptor remains the principal, if not sole, determinant of coronavirus host species range and tissue tropism.
Different SARS-CoV strains isolated from several hosts vary in their binding affinities for human ACE2 and consequently in their infectivity of human cells76,78 (Fig. 6b)
See section: Virion Structure.
See Figure 4c.
See Figure 10.
See section: Coronavirus Life Cycle – Attachment and Entry
See Figure 2.
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).
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.
See Table 2.
See Figure 8.
See section: Replicase Protein Expression
Finally, these results, combined with those from previous work (33, 44), suggest that CoVs encode at least three proteins involved in fidelity (nsp12-RdRp, nsp14-ExoN, and nsp10), supporting the assembly of a multiprotein replicase-fidelity complex, as described previously (38).
See section: Corona Life Cycle – Replication and Transcription
See Figure 1.
See section: Coronavirus Life Cycle – Assembly and Release
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