Molecular mechanisms underlying immunosuppression and inflammation caused by SARS-CoV2 proteins

PROJECT SUMMARY/Abstract: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) causes coronavirus disease2019 (COVID-19), which is characterized by acute inflammation in the lung and other organs, such as theheart and intestine. It is increasingly clear that the pathogenesis of SARS-CoV2 involves suppression ofantiviral innate immunity and induction of inflammatory responses. SARS-CoV2 suppresses induction of theantiviral type I interferons (IFNs) and, thereby, escapes from destruction by the early phase antiviral immunity.Subsequent induction of inflammatory responses drives the development of COVID-19. Understanding howSARS-CoV2 suppresses type I IFN expression and induces inflammatory responses, is crucial for designingtherapeutic approaches. Based on the studies of SARS-CoV, the close homolog of SARS-CoV2, several viralproteins have been implicated in the interplay with host immune system, contributing to the suppression of typeI IFN responses and induction of proinflammatory cytokines. The major goal of this supplementary applicationis to understand the mechanisms by which SARS-CoV2 proteins suppress antiviral innate immunity andstimulate exacerbated inflammatory responses. We will perform two specific aims. In Specific Aim 1, we will examine how SARS-CoV2 proteins suppress TBK1 signaling and antiviral innateimmunity. As described in the parent grant, TBK1 is a kinase that responds to signals from the toll-likereceptors (TLRs) and other pattern-recognition receptors (PRRs) during viral infections and mediates inductiontype I IFNs. At the same time, TBK1 negatively regulates proinflammatory cytokine induction to preventexacerbated inflammation. Our parental grant focuses on the elucidation of how TBK1 regulates TLR signalingand intestinal inflammation caused by gut microbes. In this supplementary application, we will specificallyaddress how SARS-CoV2 proteins modulate TBK1 signaling in the suppression of antiviral immunity andstimulation of inflammation. We will examine our hypothesis that suppression of TBK1 signaling by SARS-CoV2 proteins not only inhibits type I IFN production but also promotes inflammatory responses. In Specific Aim 2, we will systematically define the mechanisms by which SARS-COV2 proteins induceinflammatory responses using both cell culture and mouse models. We will examine the signaling pathwaysinvolved in SARS-CoV2-induced expression of proinflammatory cytokines in macrophages and epithelial cells.We will also examine how the Spike protein of SARS-CoV2 downregulates its cellular receptor, angiotensin-converting enzyme 2 (ACE2). Since ACE2 is a pivotal anti-inflammatory factor, we hypothesize that Spikeprotein-induced ACE2 downregulation critically contributes to the induction of lung and intestinal inflammation.We believe that these proposed studies address novel mechanisms that mediate the pathogenesis ofCOVID19 and will have important implications for COVID19 therapies.