Abstract
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.
Highlights
The betacoronaviruses of Coronaviridae family are potent human pathogens of zoonotic origin [1, 2]
ORF3a mutation was present in all group II countries which were not found in group I
Along with diverse regulating factors such as age, sex, co-morbidity complications like diabetes, cardiovascular diseases and chronic lung diseases, ORF3a mutations are linked with differential infection and mortality rate of severe acute respiratory syndrome (SARS)-CoV-2 infection (Fig. 1b)
Summary
The betacoronaviruses of Coronaviridae family are potent human pathogens of zoonotic origin [1, 2]. Human coronaviruses (CoVs) have been associated with three major outbreaks of acute respiratory disorders namely severe acute respiratory syndrome (SARS) in 2002, middle-east respiratory syndrome (MERS) in 2012 and COVID-19 in 2019 (Coronavirus disease 2019) with an overall mortality rate of 9.6%, 40% and 6.9%, respectively [1, 3-5, https://www.worldometers.info/coronavirus/]. Cell surface localisation of ORF3a in SARS-CoV potentiates viral entry within the host and has immunogenic properties [3, 9]. It is involved in pro-inflammatory cytokine and chemokine production by activating various signal transduction pathways including C-Jun N-terminal kinase (JNK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [10]. ORF3a is implicated in ion channel formation and modulates release of virus from the host cell [9]
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