SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3

Abstract

Corona virus disease 2019 (COVID-19) pathogenesis is intimately linked to the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and disease severity has been associated with compromised induction of type I interferon (IFN-I) cytokines which coordinate the innate immune response to virus infections. Here we identified the SARS-CoV-2 encoded protein, Spike, as an inhibitor of IFN-I that antagonizes viral RNA pattern recognition receptor RIG-I signaling. Ectopic expression of SARS-CoV-2 Spike blocked RIG-I mediated activation of IFNβ and downstream induction of interferon stimulated genes. Consequently, SARS-CoV-2 Spike expressing cells harbored increased RNA viral burden compared to control cells. Co-immunoprecipitation experiments revealed SARS-CoV-2 Spike associated with interferon regulatory factor 3 (IRF3), a key transcription factor that governs IFN-I activation. Co-expression analysis via immunoassays further indicated Spike specifically suppressed IRF3 expression as NF-κB and STAT1 transcription factor levels remained intact. Further biochemical experiments uncovered SARS-CoV-2 Spike potentiated proteasomal degradation of IRF3, implicating a novel mechanism by which SARS-CoV-2 evades the host innate antiviral immune response to facilitate COVID-19 pathogenesis.

Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis

“…Additional interactions with human proteins in the circulation, or even the presentation to the immune system of S protein antigenic epitopes [52] mimicking human proteins (molecular mimicry) may occur [53][54][55][56]. Reportedly, some of the near-germline SARS-CoV-2-NAbs against S receptor-binding domain (RBD) reacted with mammalian self-antigens [57], and SARS-CoV-2 S antagonizes innate antiviral immunity by targeting multiple pathways controlling interferon (IFN) production [58]. Also, a sustained elevation in T cell responses to SARS-CoV-2 mRNA vaccines has been found (data not yet peer-reviewed) in patients who suffer from chronic neurologic symptoms after acute SARS-CoV-2 infection as compared with healthy COVID-19 convalescents [59].…”

Choosing a cellular model to study SARS-CoV-2

“…Antagonizing innate host cell responses is a common strategy among viruses. The interferon pathway itself has been described as being antagonized by various mechanisms involving the SARS-CoV-2 proteins ORF3b, ORF8, ORF9b ORF6, Nsp15 and Spike (Ribero et al, 2020;Zinzula, 2021;Freitas et al, 2022). In conclusion, viral replication in an infected cell is the result of complex interactions between the host and viral proteins.…”

SARS‐CoV‐2 modulation of RIG‐I‐MAVS signaling: Potential mechanisms of impairment on host antiviral immunity and therapeutic approaches

“… 129 By acting on various molecules in the RIG‐I‐MAVS signaling pathway, SARS‐CoV‐2 viral proteins can evade host antiviral responses and promote viral replication. Since the Spike of SARS‐CoV‐2 antagonizes RIG‐I signaling, interacts with IRF3 and further blocks IFN‐I activation and induction of downstream signaling, it may serve as a key target for therapeutic intervention in COVID‐19 130 . As an immune evasion factor for SARS‐CoV‐2, Nsp1 effectively interferes with cellular translation machinery, and expanded the scope of viral infection 131 .…”