Human Coronaviruses (hCoV) cause severe respiratory syndromes like SARS, MERS, and the ongoing pandemic of Covid-19 caused by the recently identified SARS-Cov2. Human and murine studies indicate that excessive inflammation, rather than viral replication, may precipitate these infections into lethal diseases. The overarching hypothesis of this proposal is that the excessive inflammation and neutrophil recruitment triggered by IL-1? and pyroptotic cell lysis severely impair the host ability to control infection and maintain homeostasis. The corollary of this hypothesis, if proven correct, is that carefully timed inhibition of IL-1?, pyroptosis, and neutrophil proteases should be beneficial to treat Covid-19 and other hCoV infections. Increasing the significance of our study, these therapies are already approved to treat a number of human diseases, a fact that bodes well for a rapid approval to treat Covid-19 and other hCoV infections. The mouse CoV MHV-1 provides an excellent model of CoV lung infections and will be used to test our hypothesis in these specific aims:
AIM 1. Is IL-1? deleterious during CoV infection and through which mechanisms? We will test the hypothesis that excessive production of IL-1? drives neutrophil recruitment to the infected lung with consequent tissue damage. The ability of IL-1? to exacerbate the pathogenesis of MHV-1 lung infection will be studied in susceptible and resistant mouse strains treated with pharmacological inhibitors of IL-1? or in strains deficient in IL-1?. We will determine whether excessive neutrophil recruitment damages lung tissue through release of neutrophil elastase. We will also test the hypothesis that IL-1? inhibits type I and type III IFN production by stimulation of PGE2 synthesis. We will use genetic and pharmacological approaches to examine how inhibition of PGE2 production affects IFN-I and IFN-III production during MHV-1 infection. We will test whether interventions to regulate IFN-I or PGE2 in the early or late phases of the infection have opposite effect on the disease outcome.
AIM 2. Is pyroptosis beneficial or deleterious in MHV-1 infection and which inflammasome triggers cell death? We will test the hypothesis that gasdermin D-dependent pyroptosis of lung cells may affect pathogenesis of coronavirus infection in opposite ways by either restricting viral replication or exacerbating inflammation. We will test the hypothesis that pyroptosis of CoV-infected lung epithelial or endothelial cells is mediated by caspase-11. Mouse strains that lack expression of caspase-11 in lung epithelial or endothelial cells have been generated in our lab and will be used to test tissue-specific role of caspase-11 during MHV-1 infection.
While development of an effective vaccine is essential to block the present pandemic of Covid-19, therapeutic approaches to minimize morbidity and mortality caused by this and future human coronavirus infections should also be a high priority. Our studies will indicate the validity of pharmacological interventions aimed at decreasing the immunopathology of these infections and will provide mechanistic insights to develop new ones.
