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.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the current pandemic of coronavirus disease 2019 (COVID-19) and is phylogenetically related to SARS-CoV, the cause of 2002–2003 severe acute respiratory syndrome and other bat-related SARS-CoVs (Ceraolo and Giorgi, 2020)
We found that mutations in open-reading frame 8 (ORF8), in particular W45L, increase the binding with interferon regulatory factor 3 (IRF3), suggesting the important role of SARS-CoV-2 ORF8 in regulating innate immune response upon virus infection
To investigate whether ORF8 wild type (WT) or ORF8 mutants could affect their interaction with IRF3, we generated S24L, W45L, FIGURE 1 | ORF8 mutants modeling and the superimposition of ORF8 WT with ORF8 mutants. (A) ORF8 WT, (B) S24L, (C) W45L, (D) V62L, (E) L84S, (F) V62L, and L84S double mutant (G)
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the current pandemic of coronavirus disease 2019 (COVID-19) and is phylogenetically related to SARS-CoV, the cause of 2002–2003 severe acute respiratory syndrome and other bat-related SARS-CoVs (Ceraolo and Giorgi, 2020) It consists of 12 open-reading frames (ORFs), which encode 4 structural and 22 non-structural proteins IRF3 resides in the cytoplasm in inactive form When it is activated by pathogen infection, IRF3 is phosphorylated and translocates to the nucleus (Sharma et al, 2003), where it binds to the conserved sequences known as IFN stimulated response elements to induce the transcription of type I IFN genes (Kawai and Akira, 2007). Interferon-stimulated genes are activated, which are important in controlling early infections (Ivashkiv and Donlin, 2014)
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