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

Abstract

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.

Change of dominant strain during dual SARS-CoV-2 infection

“…Over 85% of Russian SARS-CoV-2 genomes submitted to GISAID (11.11.2020) belong to the GR clade and possess both of these mutations. According to different protein modeling approaches, these mutations either destabilize N protein [27] or have a neutral effect [26]. Several articles point out the association of this clade with higher mortality [30] or significant prevalence among the group of severe disease or deceased patients and also higher prevalence in females and children compared to other clades [31].…”

A rapid and cost-effective multiplex ARMS-PCR method for the simultaneous genotyping of the circulating SARS-CoV-2 phylogenetic clades

“…In this study, we attempted to validate two sets of multiplex PCR covering G, GH and GR in the first set, and V and S in the second set. Based on the available data of clade prevalence we propose to run the first set of multiplex PCR in the beginning that can confirm the most three prevalent clades (Alam, Islam, Hasan, et al, 2020). Our attempt for pentaplex and/or the quadruplex (that included the SNP variant 26144 G>T (p.G251V)) was unsuccessful, where the template regarding the variant 26144 G>T (p.G251V) did not amplify, possibly due to primer-dimer formation with higher thermodynamic stability than other variant-specific primer sets.…”

“…G clade variant was dominant in Europe (Korber et al, 2020) and USA (Brufsky, 2020) on the beginning of the pandemic that caused high mortality in USA. This mutation variant was gradually circulating in Southeast Asia (Alam, Islam, Hasan, et al, 2020; and Oceania (Mercatelli & Giorgi, 2020). Among the two derivative of G clade (GR and GH) that emerged at the end of February 2020, GR mutant are now the leading type that cause more than one-third of infection globally (Mercatelli & Giorgi, 2020).…”

“…Researchers have demonstrated that the predominant mutations may attribute to virulence (Alam, Islam, Hasan, et al, 2020;Rahman et al, 2020;Q. Wang et al, 2020).…”

A rapid and cost‐effective multiplex ARMS‐PCR method for the simultaneous genotyping of the circulating SARS‐CoV‐2 phylogenetic clades

“…9,13 G clade variant was dominant in Europe 14 and United States 15 on the eve of the pandemic, which caused high mortality in the United States. This mutation variant has gradually been circulated in Southeast Asia 9,16 and Oceania. 12 On the contrary, GR and GH clades emerged at the end of February 2020, and GR mutants are now the leading type that causes more than one-third of infection globally.…”