Investigation of the cell-intrinsic immune response and the antiviral efficacy of interferons against SARS-CoV2

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The novel coronavirus, SARS-CoV2, is a plus-strand RNA virus. RNA virus infection very generally engages molecular sensors of the cell-intrinsic innate immune system, so called pattern recognition receptors (PRRs), most importantly of the RIG-I-like receptor (RLR) family. RLRs trigger a signaling cascade culminating in the transcription, production and secretion of inflammatory cytokines (via the transcription factor NFκB) and antiviral cytokines, most prominently type I and III interferons (IFNs) (via IRF3). Additionally, strong stimulation of those antiviral pathways also leads to the induction of cell death, potentially generating danger signals (DAMPs) that further stimulate inflammatory processes in the tissue. In the specific case of SARS-CoV2 infection, we and others have shown that the virus (and close relatives) strongly inhibits the activation of IRF3 and, hence, the production of IFNs. In contrast, it does not block activation of NFκB and the induction of an inflammatory transcriptional program. This selective blockage of the antiviral branch of cell-intrinsic defense pathways leads to a strongly skewed immune response, likely contributing to the observed induction of an inflammatory “cytokine storm”, which together with direct tissue destruction by virus-induced cytopathy most likely forms the basis of immune hyperactivation, eventually leading to the excessive inflammation and immunopathology characterizing COVID-19. If this is the case, innate immune responses rather play a detrimental role in the development of COVID-19, but fail to contain viral replication and spread. A prospective therapeutic regimen may therefore be the pharmacological inhibition of PRR signaling, preventing the production of inflammatory cytokines and possibly dampening the induction of epithelial cell death. Combining such inhibition with the administration of exogenous IFNs could provide a highly efficacious two-pronged therapeutic option, impacting both, viral replication and the inflammatory basis COVID-19.In the proposed project, we are going to characterize the signaling pathways involved in the induction of programmed cell death and the activation of inflammatory transcriptional programs. We will further investigate the antiviral efficacy of different IFN types against SARS-CoV2, including the understudied type I IFN kappa. The collective results from this one-year research program will then inform us about the feasibility of the proposed therapeutic approach and form the basis for longer-term in-depth studies on antiviral immunity in SARS-CoV2.