Evolving Infection Paradox of SARS-CoV-2: Fitness Costs Virulence?

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is continuously spreading worldwide at an unprecedented scale in 2020. Within the first six months of the COVID-19 pandemic, it has evolved into six clades according to GISAID where three (G, GH, and GR) are now globally prevalent (>75%). Here we report the prevalence of these dominant clades, both individually and in combination, with disease progression and death-case scenario that leads to infer fitness of the SARS-CoV-2 by compromising its virulence. Unlike G or GH clades, the GR clade strains represent a significant negative association with the death-case ratio (R= -0.558, p=0.019). Docking analysis revealed the molecular scenario behind more infectiousness of S protein D614G mutation and reasoned more favorable binding of G614 with the elastase-2. Viral RNA-dependent-RNA-polymerase (RdRp) mutation p.P323L facilitated significantly higher (p<0.0001) genome-wide mutations because more flexible RdRp (mutant)-NSP8 interaction may accelerate replication. Superior RNA stability and structural variation at NSP3:C241T might change the protein’s conformation with a speculated impact on 5'UTR, nucleocapsid, and replication complex interactions. Another silent 5'UTR:C241T mutation might affect translational efficiency and viral packaging. These G-featured coevolving mutations might together increase the viral load, quicker cell death, and potentially a stronger immune response within the host, hence can modulate intra-host genomic plasticity. In addition, viroporin ORF3a:p.Q57H mutation of GH-clade prevents ion permeability by constricting the channel pore more tightly due to additional ionic interaction with the cysteine (C81) of transmembrane-domain-2, which possibly reduces viral release and immune response. GR strains (four G clade mutations with N:p.RG203-204KR) would have maintained more stability with stronger RNA interaction, a flexible linker region, and the molecular effect of hypo-phosphorylation at SR-stretch. These empirical assumptions need further retrospective and prospective studies to understand detailed molecular and evolutionary events featuring the fitness and virulence of SARS-CoV-2.
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