SARS-related coronavirus

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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
host cells
cultured in the lab
Virus classification Edit this 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
Synonyms
  • SARS coronavirus
  • SARS-related coronavirus
  • Severe acute respiratory syndrome coronavirus[1]

Severe-acute-respiratory-syndrome–related coronavirus (SARSr-CoV or SARS-CoV)

Himalayan palm civets, which were likely ancestors of SARS-CoV-1.[2][4][5][6]

These

positive-sense single-stranded RNA viruses enter host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor.[7] The SARSr-CoV species is a member of the genus Betacoronavirus and the only species of the subgenus Sarbecovirus (SARS Betacoronavirus).[8][9]

The SARS-related coronavirus was one of several viruses identified by the

medicines. This prediction came to pass with the COVID-19 pandemic.[10][11]

Classification

SARS-related coronavirus is a member of the genus Betacoronavirus (group 2) and monotypic of the subgenus Sarbecovirus (subgroup B).[12] Sarbecoviruses, unlike embecoviruses or alphacoronaviruses, have only one papain-like proteinase (PLpro) instead of two in the open reading frame ORF1ab.[13] 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.[14][15]

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

SARS-CoV-2.[17][7] 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.[2]

Genome

SARS-CoV

The SARS-related

nucleotides in the 5'UTR and 342 nucleotides in the 3'UTR.[18]

The 5' methylated cap and 3' polyadenylated tail allows the

polyproteins.[18]

Function of SARSr-CoV
genome proteins
Protein Function[21][22][23][24]
ORF1ab
P0C6X7 		Replicase/transcriptase polyprotein (pp1ab)
(nonstructural proteins)
ORF2
P59594 		Spike (S) protein, virus binding and entry
(structural protein)
ORF3a
P59632		 Interacts with S, E, M structural proteins;
Bax, p53, and p38 MAP kinase
ORF3b
P59633		 Upregulates cytokines and chemokines by RUNX1b;
Inhibits Type I IFN production and signaling;
Induces apoptosis and cell cycle arrest;
ORF3c
P0DTG1		 Unknown; first identified in SARS-CoV-2 but also present in SARS-CoV
ORF3d
P0DTG0		 Novel gene in SARS-CoV-2, of unknown function
ORF4
P59637 		Envelope (E) protein, virus assembly and budding
(structural protein)
ORF5
P59596 		Membrane (M) protein, virus assembly and budding
(structural protein)
ORF6
P59634		 Enhances cellular DNA synthesis;
Inhibits Type I IFN production and signaling
ORF7a
P59635		 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
ORF7b
Q7TFA1		 Unknown
ORF8a
Q7TFA0
 Induces apoptosis through mitochondria pathway
ORF8b
Q80H93
 Enhances cellular DNA synthesis, also known as X5.
ORF9a
P59595 		Nucleocapsid (N) protein, viral RNA packaging
(structural protein)
ORF9b
P59636		 Induces apoptosis
ORF9c
Q7TLC7		 Also known as ORF14; function unknown and may not be protein-coding
ORF10
A0A663DJA2		 Novel gene in SARS-CoV-2, of unknown function; may not be protein-coding
SARS-CoV
proteins unless they are specific to SARS-CoV-2

The functions of several of the viral proteins are known.

accessory proteins, many with no known homologues. The different functions of the accessory proteins are not well understood.[25]

SARS coronaviruses have been genetically engineered in several laboratories.[27]

Phylogenetics

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.[28][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

Rhinolophus ferrumequinum, North Jeolla, South Korea[29]

Jilin[30]

Bat SARS CoV Rf1, 87.8% to SARS-CoV-1,

Rhinolophus ferrumequinum, Yichang, Hubei[31]

BtCoV HKU3, 87.9% to SARS-CoV-1,

Rhinolophus sinicus, Hong Kong and Guangdong[32]

Rhinolophus affinis, Baoshan, Yunnan[33]

Bat SARS-CoV/Rp3, 92.6% to SARS-CoV-1,

Rhinolophus pearsoni, Nanning, Guangxi[31]

Bat SL-CoV YNLF_31C, 93.5% to SARS-CoV-1,

Rhinolophus ferrumequinum, Lufeng, Yunnan[34]

Bat SL-CoV YNLF_34C, 93.5% to SARS-CoV-1,

Rhinolophus ferrumequinum, Lufeng, Yunnan[34]

Rhinolophus sinicus, Kunming, Yunnan[35]

Rhinolophus sinicus, Kunming, Yunnan[35]

Rhinolophus sinicus Kunming, Yunnan[36]

Paguma larvata, market in Guangdong, China[32]

SARS-CoV-1

SARS-CoV-2, 79% to SARS-CoV-1[37]


SARS-CoV-2 related

A phylogenetic tree based on whole-genome sequences of SARS-CoV-2 and related coronaviruses is:[38][39]

SARS‑CoV‑2 related coronavirus

(

Rhinolophus cornutus, Iwate, Japan[40]

Bat

Rhinolophus pusillus, Zhoushan, Zhejiang[41]

Bat SL-ZC45, 88% to SARS-CoV-2, Rhinolophus pusillus, Zhoushan, Zhejiang[41]

Manis javanica, smuggled from Southeast Asia[42]

Pangolin SARSr-CoV-GD, 90.1% to SARS-CoV-2, Manis javanica, smuggled from Southeast Asia[43]

Bat RshSTT182, 92.6% to SARS-CoV-2,

Steung Treng, Cambodia[44]

Bat RshSTT200, 92.6% to SARS-CoV-2, Rhinolophus shameli, Steung Treng, Cambodia[44]

(Bat)

Chachoengsao, Thailand[39]

(Bat)

Rhinolophus malayanus, Mengla, Yunnan[45]

(Bat)

Xishuangbanna, Yunnan[38]

(Bat)

Rhinolophus affinis, Mojiang, Yunnan[46]

(Bat)

Rhinolophus malayanus, Vientiane, Laos[47]

SARS-CoV-2

SARS-CoV-1
, 79% to SARS-CoV-2


Morphology

virion.[48]
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.[49] 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.[50]

The

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.[52][53]

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.[54][55] The lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host.[56]

Life cycle

SARS-related coronavirus follows the replication strategy typical of all coronaviruses.[19][57]

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.[58] The spike protein receptor binding domain (RBD) recognizes and attaches to the angiotensin-converting enzyme 2 (ACE2) receptor.[7] 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.[59]

The attachment of sarbecoviruses to ACE2 has been shown to be an

evolutionarily conserved feature, present in many species of the taxon.[60]

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.[59]

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.[61][62] 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.[63]

Genome translation

Function of coronavirus
nonstructural proteins (nsps)[64]
Protein Function
nsp1 Promotes host mRNA degradation, blocks host translation;[65]
blocks innate immune response
nsp2 Binds to prohibitin proteins;
unknown function
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;
unknown function
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
nsp11 Unknown function
nsp12 RNA-dependent RNA polymerase (RdRp)
nsp13 RNA helicase, 5′ triphosphatase
nsp14 N7 Methyltransferase, 3′-5′ exoribonuclease (ExoN); N7 MTase adds 5′ cap, ExoN proofreads genome
nsp15 Endoribonuclease (NendoU)
nsp16 2′-O-Methyltransferase (2-O-MT); protects viral RNA from MDA5

After fusion the nucleocapsid passes into the

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.[66] The ribosomal frameshift allows for the continuous translation of ORF1a followed by ORF1b.[67]

The polyproteins contain their own

RNA helicase, and exoribonuclease (ExoN).[67]

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."[68]

Replication and transcription

replicase-transcriptase complex of a coronavirus. RdRp for replication (red), ExoN for proofreading (dark blue), ExoN cofactor (yellow), RBPs to avoid secondary structure (light blue), RNA sliding clamp for processivity and primase domain for priming (green/orange), and a helicase
to unwind RNA (downstream).

A number of the nonstructural replication proteins coalesce to form a multi-protein replicase-transcriptase complex (RTC).[67] 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.[64]

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.[64] The coronaviruses require the increased fidelity and processivity during RNA synthesis because of the relatively large genome size in comparison to other RNA viruses.[69]

One of the main functions of the replicase-transcriptase complex is to transcribe the viral genome. RdRp directly mediates the

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.[70]

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.[70]

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.[71]

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).[72] Human SARS-CoV appears to have had a complex history of recombination between ancestral coronaviruses that were hosted in several different animal groups.[72][73]

Assembly and release

Golgi intermediate compartment. There, the M proteins direct most protein-protein interactions required for assembly of viruses following its binding to the nucleocapsid.[74]

Progeny viruses are released from the host cell by exocytosis through secretory vesicles.[74]

See also

Notes

  1. ^ 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.

References

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    . 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).
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Further reading

External links
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