ORF3a mutation associated with higher mortality rate in SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently caused acute respiratory distress syndrome affecting more than 200 countries with varied mortality rate. Successive genetic variants of SARS-CoV-2 become evident across the globe immediately after its complete genome sequencing. Here, we found a decent association of SARS-CoV-2 ORF3a mutation with higher mortality rate. Extensive in silico studies revealed several amino acid changes in ORF3a protein which ultimately leads to diverse structural modifications like B cell epitope loss, gain/loss of phosphorylation site and loss of leucine zipper motif. We could further relate these changes to the enhanced antigenic diversity of SARS-CoV-2. Through protein-protein network analysis and functional annotation studies, we obtained a close federation of ORF3a protein with host immune response via divergent signal transduction pathways including JAK-STAT, chemokine and cytokine-related pathways. Our data not only unveil the fairly appreciable association of ORF3a mutation with higher mortality rate, but also suggest a potential mechanistic insight towards the immunopathogenic manifestation of SARS-CoV-2 infection.