In silico analyses on the comparative sensing of SARS-CoV-2 mRNA by the intracellular TLRs of human.

Choudhury, Abhigyan; Chandra Das, Nabarun; Patra, Ritwik; Mukherjee, Suprabhat

COVID-19 pandemic caused by SARS-CoV-2 has already resulted huge setback to mankind in terms of millions of deaths while the unavailability of appropriate therapeutic strategy has made the scenario much more severe. Toll-like receptors (TLRs) are the crucial mediators and regulators of host immunity and the role of human cell surface TLRs in SARS-CoV-2 induced inflammatory pathogenesis has been demonstrated recently. However, the functional significance of the human intracellular TLRs including TLR3,7,8 and 9 is yet unclear. Hitherto, the involvement of these intracellular TLRs in inducing proinflammatory responses in COVID-19 has been reported but the identity of the interacting viral RNA molecule(s) and the corresponding TLRs have not been explored. This study is hoped to rationalize the comparative binding of the major SARS-CoV-2 mRNAs to the intracellular TLRs, considering the solvent-based force-fields operational in the cytosolic aqueous microenvironment that predominantly drives these interactions. Our in-silico study on the binding of all mRNAs with the intracellular TLRs depicts that the mRNA of NSP10, S2, and E proteins of SARS-CoV-2 are possible virus-associated molecular patterns that bind to TLR3, TLR9, and TLR7 respectively and trigger downstream cascade reactions. Intriguingly, binding of the viral mRNAs resulted in variable degrees of conformational changes in the ligand-binding domain of the TLRs ratifying the activation of the downstream inflammatory signaling cascade. Taken together, the current study is a maiden report to describe the role of TLR3, 7, and 9 in COVID-19 immunobiology and could serve as useful targets for the conception of therapeutic strategy against the pandemic. This article is protected by copyright. All rights reserved.