Characterization of SARS-CoV-2 Evasion: Interferon Pathway and Therapeutic Options

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. SARS-CoV-2 is characterized by an important capacity to circumvent the innate immune response. The early interferon (IFN) response is necessary to establish a robust antiviral state. However, this response is weak and delayed in COVID-19 patients, along with massive pro-inflammatory cytokine production. This dysregulated innate immune response contributes to pathogenicity and in some individuals leads to a critical state. Characterizing the interplay between viral factors and host innate immunity is crucial to better understand how to manage the disease. Moreover, the constant emergence of new SARS-CoV-2 variants challenges the efficacy of existing vaccines. Thus, to control this virus and readjust the antiviral therapy currently used to treat COVID-19, studies should constantly be re-evaluated to further decipher the mechanisms leading to SARS-CoV-2 pathogenesis. Regarding the role of the IFN response in SARS-CoV-2 infection, in this review we summarize the mechanisms by which SARS-CoV-2 evades innate immune recognition. More specifically, we explain how this virus inhibits IFN signaling pathways (IFN-I/IFN-III) and controls interferon-stimulated gene (ISG) expression. We also discuss the development and use of IFNs and potential drugs controlling the innate immune response to SARS-CoV-2, helping to clear the infection.

Generation and functional analysis of defective viral genomes during SARS-CoV-2 infection

“…DVGs from RSV and influenza can function as primary triggers to directly stimulate type I IFN production through RIG-I like receptors (Sun and López 2017). It is previously reported that SARS-CoV-2 RNAs can be recognized by MDA5 (Thorne, Reuschl et al 2021, Znaidia, Demeret et al 2022) and we showed that the expression of MDA5 (IFIH1) was elevated in DVG+ cells at 2 dpi (Fig. 6C).…”

“…Alternatively, if DVGs do not directly stimulate IFN production, they can suppress the expression of viral-encoding IFN antagonists by large deletions, resulting in an earlier and higher IFN expression in DVG+ cells. Indeed, IFN antagonists are encoded in NSP1, NSP3, NSP5, NSP12, NSP13, NSP14, NSP15, ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8, ORF9b, N, and M (Lei, Dong et al 2020, Xia, Cao et al 2020, Han, Zhuang et al 2021, Wong, Cheung et al 2022, Znaidia, Demeret et al 2022) and most of them are within the deletion regions based on our conserved genomic hotspots for DVG recombination sites (Fig. 2A and 2B).…”

Innate immunity, cytokine storm, and inflammatory cell death in COVID-19

“…ORF9b also blocks the TLR3-TRIF pathway [ 135 ]. Nearly all the SARS-CoV-2 proteins have been suggested to block IFN production and signaling at various points in the IFN pathway, and this has been extensively characterized [ 136 ]. Aside from blocking TLR and RLR signaling specifically, ORF6 prevents nuclear localization of the transcription factor signal transducer and activator of transcription 1 (STAT1), which is needed for IFN production [ 137 ].…”

The role of SARS-CoV-2 accessory proteins in immune evasion

“…A decrease in IFN-promoter activity mediated by MAVS. TRIM59 [10] , [15] , [16] , [17] , [18] , [19] , [20] , [21] ORF3b 1. Restricting the nuclear translocation of IRF3.…”