SARS-CoV-2

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [[1]]; Associate Editor(s)-in-Chief: Syed rizvi, M.B.B.S[1]

The Coronavirus disease-2019 (COVID-19), is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 forms a distinct lineage with bat SARS-like coronaviruses . The virus is closely related (96.3%) to bat coronavirus RaTG13, based on phylogenetic analysis, that belong to the order Nidovirales, family Coronaviridae, genus Betacoronavirus, and subgenus Sarbecovirus . Coronaviruses are enveloped, single-stranded RNA viruses that can infect a wide range of hosts including avian, wild, domestic mammalian species, and humans. Coronaviruses are well known for their ability to mutate rapidly, alter tissue tropism, cross the species barrier, and adapt to different epidemiological situations. Six human coronaviruses have been reported since the 1960s; OC43, 229E, NL63, HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). First case of COVID-19 was reported in Wuhan, Hubei province, China, in December 2019, associated with the Huanan Seafood Wholesale Market. On March 11, 2020 the Novel Coronavirus Disease, COVID-19, was declared a pandemic by the World Health Organization

• SARS-CoV-2 belong to the order nidovirale, family coronaviridae.^[1]
• Coronaviridae is classified into two subfamilies.
  • Torovirinae
  • Coronavirinae
• Coronavirinae is further classified on the basis of phylogenetic analysis and genome structure into four genera:
  • Alpha coronavirus (αCoV).
  • Beta coronavirus (βCoV).
  • Gamma coronavirus (γCoV).
  • Delta coronavirus (δCoV), which contain 17, 12, 2, and 7 unique species, respectively (ICTV 2018).
• CoV-2 falls under beta coronavirus.

• Spike (S) Protein ^[2][3]
  • Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases.
  • Early studies indicate that SARS-CoV-2 uses the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2) for entry and transmembrane protease serine 2 (TMPRSS2) for S protein priming.^[7][8]
  • The spike (S) glycoprotein is a type I transmembrane glycoprotein that plays an important role in mediating viral infection.
  • The S proteins consist of two subunits, S1 and S2.
  • The S1 subunit binds the cellular receptor through its receptor-binding domain (RBD), followed by conformational changes in the S2 subunit, which allows the fusion peptide to insert into the host target cell membrane.^[9]

• Envelope (E) Protein^[4]
  • The CoV envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus’ life cycle, such as assembly, budding, envelope formation, and pathogenesis.^[10]
  • Recent studies have expanded on its structural motifs and topology, its functions as an ion-channelling viroporin, and its interactions with both other CoV proteins and host cell proteins.^[11]
  • Recombinant CoVs lacking E exhibit significantly reduced viral titres, crippled viral maturation, or yield propagation incompetent progeny, demonstrating the importance of E in virus production and maturation.^[12]

• Membrane (M) Protein ^[5]
  • The CoV membrane (M) protein is a component of the viral envelope that plays a central role in virus morphogenesis and assembly via its interactions with other viral proteins.
  • M is located among the S proteins in the virus envelope along with small amounts of E and is the primary driver of the virus budding process.
  • During assembly of the authentic virion M interacts with itself, with the nucleocapsid protein N, with E and with the S protein.
  • The M protein has dominant cellular immunogenicity and elicits a strong humoral response which suggests it could serve as a potential target in vaccine design.^{[14] [15]}

• Nucleocapsid (N) Protein^[16]
  • The primary function of the nucleocapsid (N) protein is to package the viral RNA genome within the viral envelope into a ribonucleoprotein (RNP) complex called the capsid.
  • Ribonucleocapsid packaging is a fundamental part of viral self-assembly and replication.
  • Additionally, the N-protein of the SARS-CoV-2 affects host cell responses and may serve regulatory roles during its viral life cycle.
    

• The attachment of the virion to the host cell is associated with the interactions between the S protein and its receptor.
• The sites of receptor binding domains (RBD) within the S1 region of a coronavirus (SARS-CoV-2) S protein is at the C Terminus.^[18]
• SARS-CoV use angiotensin-converting enzyme 2 (ACE2) as their receptor^[19]
• After binding to the receptor, the virus next step is to gain access to the host cell cytosol.
• This is generally done by cathepsin,TMPRRS2 or some other protease. This is followed by fusion of the viral and cellular membranes.
• S protein cleavage occurs at two sites within the S2 portion of the protein, with the first cleavage important for separating the RBD (Receptor binding domain) and fusion domains of the S protein ^[20] and the second for exposing the fusion peptide (cleavage at S2′).
• Fusion occurs within acidified endosomes.
• Cleavage at S2′ exposes a fusion peptide that inserts into the membrane, which is followed by joining of two heptad repeats in S2 forming an antiparallel six-helix bundle^[21].The formation of this bundle allows for the mixing of viral and cellular membranes, resulting in fusion and ultimately release of the viral genome into the cytoplasm.

• The next step in the coronavirus lifecycle is translation and assembly of the viral replicase complexes from the virion genomic RNA.

• The translation and assembly of the viral replicase complexes is followed by viral RNA synthesis.
• Viral RNA synthesis produces both genomic and sub-genomic RNAs.
• Sub-genomic RNAs serve as mRNAs for the structural and accessory genes which reside downstream of the replicase polyproteins. All positive-sense sub-genomic RNAs are 3′ co-terminal with the full-length viral genome and thus form a set of nested RNAs, a distinctive property of the order Nidovirales. Both genomic and sub-genomic RNAs are produced through negative-sense intermediates. These negative-strand intermediates are only about 1 % as abundant as their positive-sense counterparts and contain both poly-uridylate and anti-leader sequences.^[22]

• After replication and transcription, the structural proteins of virus ( S,M,E) are translated and then inserted into endoplasmic reticulum. From endoplasmic reticulum they are taken to endoplasmic reticulum-Golgi intermediate compartment.^[23]
• Here the N protein encapsidate the viral genome, and bud into membranes of the endoplasmic reticulum-Golgi intermediate compartment containing viral structural proteins, thus forming mature virion.^[24]
• Following assembly, virions are transported to the cell surface in vesicles and released by exocytosis.
  

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preferentially infects cells in the respiratory tract, which is lung alveolar epithelial cell .^[25][26]
• SARS-CoV-2 can be detected in multiple organs, including the lungs, heart, liver, brain, pharynx and kidneys.^[27]
• Highest levels of SARS-CoV-2 copies per cell were presumed to be detected in the respiratory tract, and lower levels were detected the kidneys, liver, heart, brain, and blood.
  • These findings indicate a broad organotropism of SARS-CoV-2.^[28]

• Current evidences suggest that the evolutional origin of SARS-CoV-2 is from bat virus an intermediate host between bats and human might exist.^[29][30]
• Potential intermediate host for SARS-CoV-2 can be pangolin.
• Novel coronaviruses representing two sub-lineages related to SARS-CoV-2 were found in the samples of malytan pangolins.^[31]
• The similarity of SARS-CoV-2 to these identified coronaviruses from pangolins is approximately 85.5% to 92.4% in genomes, lower than that to the bat coronavirus RaTG13 (96.2%) 14,62.
• However, the receptor-binding domain of S protein from one sub-lineage of the pangolin coronaviruses shows 97.4% similarity in amino acid sequences to that of SARS-CoV-2, even higher than that to RaTG13 (89.2%).^[32]

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