Novel Mechanisms of Innate Immune System Regulation Following SARS-CoV-2 Exposure

Abstract The SARS-CoV-2 pandemic has wreaked havoc on our public health system and economy. The outcome of SARS-CoV-2 infection is determined by host-virus interactions and anti-viral immune responses. A delicate balance must be struck between mounting a vigorous immune response to eradicate the virus and quelling overactive inflammation to protect the host. Indeed, overzealous inflammation is associated with the “cytokine storm” reported in an alarming number of COVID-19 patients and underlies the Multisystem Inflammatory Syndrome reported in pediatric cases. Initial studies have suggested that SARS-CoV-2 is capable of inhibiting type-I interferon signaling, hijacking cell death processes, and inducing robust pro-inflammatory cytokine production in patients with poor outcomes. Here, we confirm many of these previous findings using whole genome transcriptomics approaches in human patients and complementary mechanistic studies using SARS-CoV-2 infection in K18-hACE2 mice. Using these approaches, we further identify 12 critical cytokines that appear to be associated with the overzealous immune response in COVID-19 patients. Further studies and pathway analysis identified members of the NBD-LRR (NLR) family of pattern recognition receptors that regulate distinct mechanisms underlying overzealous inflammation. Together, these data provide insight into novel mechanisms of immune system regulation that appear responsible for modulating several aspects of SARS-CoV-2 pathobiology.