Defective ORF8 dimerization in SARS-CoV-2 delta variant leads to a better adaptive immune response due to abrogation of ORF8-MHC1 interaction

Abstract

In India, during the second wave of the COVID-19 pandemic, the breakthrough infections were mainly caused by the SARS-COV-2 delta variant (B.1.617.2). It was reported that, among majority of the infections due to the delta variant, only 9.8% percent cases required hospitalization, whereas only 0.4% fatality was observed. Sudden dropdown in COVID-19 infections cases were observed within a short timeframe, suggesting better host adaptation with evolved delta variant. Downregulation of host immune response against SARS-CoV-2 by ORF8 induced MHC-I degradation has been reported earlier. The Delta variant carried mutations (deletion) at Asp119 and Phe120 amino acids which are critical for ORF8 dimerization. The deletions of amino acids Asp119 and Phe120 in ORF8 of delta variant resulted in structural instability of ORF8 dimer caused by disruption of hydrogen bonds and salt bridges as revealed by structural analysis and MD simulation studies. Further, flexible docking of wild type and mutant ORF8 dimer revealed reduced interaction of mutant ORF8 dimer with MHC-I as compared to wild-type ORF8 dimer with MHC-1, thus implicating its possible role in MHC-I expression and host immune response against SARS-CoV-2. We thus propose that mutant ORF8 of SARS-CoV-2 delta variant may not be hindering the MHC-I expression thereby resulting in a better immune response against the SARS-CoV-2 delta variant, which partly explains the possible reason for sudden drop of SARS-CoV-2 infection rate in the second wave of SARS-CoV-2 predominated by delta variant in India. Armi M. Chaudhari and Indra Singh authors are contributed equally to this work.

How SARS-CoV-2 alters the regulation of gene expression in infected cells†

“…16,[25][26][27] Recently, the role of ORF8 has been particularly pointed out. [28][29][30] Indeed, this small water-soluble immunoglobulin-(Ig)-like protein is interfering with the immune system response, particularly by interacting with monocytes. 31 The structure of ORF8 in bat and human coronaviruses has also been resolved, and the molecular bases of its perturbation of the immune response, which proceeds through the formation of sulphurbridge mediated large scale aggregates, has been discussed.…”

“…31 The structure of ORF8 in bat and human coronaviruses has also been resolved, and the molecular bases of its perturbation of the immune response, which proceeds through the formation of sulphurbridge mediated large scale aggregates, has been discussed. 30,32 However, the importance of ORF8 goes way beyond this direct Ig-like effect. More recently, it has been shown that ORF8 is able to penetrate the nuclear membrane and accumulates in the nucleus.…”

“…31 The structure of ORF8 in bat and human coronaviruses has also been resolved, and the molecular bases of its perturbation of the immune response, which proceeds through the formation of sulphur-bridge mediated large scale aggregates, has been discussed. 30,32…”

How SARS-CoV-2 Alters the Regulation of Gene Expression in Infected Cells

“…35 The structure of ORF8 in bat and human coronaviruses has also been resolved, and the molecular bases of its perturbation of the immune response, which proceeds through the formation of sulfurbridge mediated large scale aggregates, have been discussed. 34 However, the importance of ORF8 goes way beyond this direct Ig-like effect. More recently, it has been shown that ORF8 is able to penetrate the nuclear membrane and accumulates in the nucleus.…”

“… 35 The structure of ORF8 in bat and human coronaviruses has also been resolved, and the molecular bases of its perturbation of the immune response, which proceeds through the formation of sulfur-bridge mediated large scale aggregates, have been discussed. 34 , 36 …”