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SARS-COV2 Replication

Like all viruses, the tendency to replicate in coronaviruses is crucially determined by the
functional capacity of its host cell. The ability of SARS-COV2 to replicate efficiently in host lung tissue is based on the presence of its functional receptor, the metalloproteinase human Angiotensin-Converting Enzyme 2(hACE2), which is highly expressed on lung cells as well
as others; heart, kidney and gastrointestinal tract (GIT).

virions and hACE2 receptor. Source:

The virus enters host cells 293/hACE2
mainly via endocytosis by attachment of its S glycoprotein with cell surface ACE2 receptors. The S glycoprotein has two subunits, S1 and S2. S1 determines the viral host-range and cellular tropism via receptor binding domain (RBD), while S2 facilitates virus-cell membrane fusion by two tandem domains, heptad repeats 1(HR1) and heptad repeats 2 (HR2). Initially, there is binding of viral S1 glycoproteins with Receptor Binding Protein (RBD) on hACE2 cell surface receptors.

hACE2 molecule illustrated. Source:

Type II Membrane serine proteases (TMPRSS2) cleavage mediates the activation and fusion of SARS-COV2 to its receptor via inducing receptor-dependent syncytium formation which is necessary for S protein activation. Nonetheless, SARS-COV2 protein could be triggered upon receptor binding without exogenous protease (trypsin) priming. Upon successful activation, a cascade of downstream events by Two-pore channel subtype 2 (TPC2)
and PIKfyve enzyme initiates the synthesis of Phosphatidylinositol-3,5-biphosphate
(PI(3,5)Pā‚‚), which serves as the regulator of early and late endosome formation.

cell surface proteins(ACE2 and TMPRSS2) interaction with SARS-COV2 S glycoproteins. Markus Hoffmann/German Primate Centre

Cathepsin-L found in cell lysosome facilitates SARS-COV2 entry via endocytosis after endosome formation. On entry, the virus attaches to host ribosomes and begins synthesis of viral proteins. The genomic RNA of coronaviruses (approx. 30,000 nucleotides) encodes structural and non-structural proteins (replicase-transcriptase proteins) of the virus that have critical roles in viral RNA synthesis. At least, one structural protein(sp) and non structural protein 2 (nsp2) are involved in RNA synthesis. The translation of viral structural proteins (spike, membrane and envelope) occurs at the endoplasmic reticulum. The expression of the replicase-transcriptase
protein genes is mediated by genomic RNA. The replicase-transcriptase proteins are encoded in open-reading frame 1a (ORF1a) and ORF1b and are synthesized by two large polyproteins, pp1a and pp1ab. The synthesis of pp1ab involves programmed ribosomal frameshifting during translation of ORF1a. During and after synthesis, these polyproteins are cleaved by virus encoded proteinases with papain-like (PLpro) and chymotrypsin-like folds into 16 proteins. NSP1 to NSP11 are encoded in ORF1a, and NSP12 to NSP16 are encoded in ORF1b.

SARS-COV2 structure showing structural and non-structural proteins.

The replicase-transcriptase proteins together with other viral proteins (nucleocapsid) and cellular proteins, assemble into membrane-bound replication-transcription complexes (RTC) at the ER-Golgi intermediate compartment. These complexes accumulate at perinuclear
regions and are associated with double-membrane vesicles. Hydrophobic transmembrane domains are present in NSP3, NSP4 and NSP6 likely to serve as anchor for nascent pp1a and pp1ab to membranes. The virion containing vesicles (Golgi vesicle) then fuse with the plasma
membrane of the cell for exocytosis. The released mature virion attacks another cell, and the cycle is repeated.

by Wilson Gbedema (Editor) 



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