Mutations in SARS-CoV-2 ORF8 Altered the Bonding Network With Interferon Regulatory Factor 3 to Evade Host Immune System

Farooq Rashid; Muhammad Suleman; Abdullah Shah; Emmanuel Enoch Dzakah; Haiying Wang; Shuyi Chen; Shixing Tang

doi:10.3389/fmicb.2021.703145

Mutations in SARS-CoV-2 ORF8 Altered the Bonding Network With Interferon Regulatory Factor 3 to Evade Host Immune System

Front Microbiol. 2021 Jul 16:12:703145. doi: 10.3389/fmicb.2021.703145. eCollection 2021.

Authors

Farooq Rashid^{1

2}, Muhammad Suleman³, Abdullah Shah⁴, Emmanuel Enoch Dzakah^{1

5}, Haiying Wang², Shuyi Chen², Shixing Tang^{1

2

6}

Affiliations

¹ Dermatology Hospital, Southern Medical University, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
³ Center for Biotechnology and Microbiology, University of Swat, Mingora, Pakistan.
⁴ Department of Biotechnology, Shaheed Benazir Bhutto University, Sheringal, Pakistan.
⁵ Department of Molecular Biology and Biotechnology, School of Biological Sciences, College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana.
⁶ Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been continuously mutating since its first emergence in early 2020. These alterations have led this virus to gain significant difference in infectivity, pathogenicity, and host immune evasion. We previously found that the open-reading frame 8 (ORF8) of SARS-CoV-2 can inhibit interferon production by decreasing the nuclear translocation of interferon regulatory factor 3 (IRF3). Since several mutations in ORF8 have been observed, therefore, in the present study, we adapted structural and biophysical analysis approaches to explore the impact of various mutations of ORF8, such as S24L, L84S, V62L, and W45L, the recently circulating mutant in Pakistan, on its ability to bind IRF3 and to evade the host immune system. We found that mutations in ORF8 could affect the binding efficiency with IRF3 based on molecular docking analysis, which was further supported by molecular dynamics simulations. Among all the reported mutations, W45L was found to bind most stringently to IRF3. Our analysis revealed that mutations in ORF8 may help the virus evade the immune system by changing its binding affinity with IRF3.

Keywords: IRF3; MD simulation; ORF8 mutants; SARS-CoV-2; protein–protein docking.