Reovirus induction of host inflammatory responses

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PROJECT SUMMARY Viral myocarditis is a significant cause of morbidity and mortality worldwide, particularly in children and young adults. Despite the clinical importance of viral myocarditis, the mechanisms by which viruses cause myocarditis are poorly understood. The overall objective of experiments described in this application is to define viral and host determinants that contribute to the development of viral myocarditis. Work proposed in this application uses mammalian orthoreovirus (reovirus), which is a longstanding model for studying viral cardiac infections in neonates. We recently identified a potently myocarditic reovirus strain (T1L/T3DM2) that is highly lethal in neonatal mice. Our preliminary data indicate that the virulence of T1L/T3DM2 is markedly diminished in mice lacking key components of pyroptotic cell death pathway. In this application, we will explore how pyroptosis potentiates reovirus myocarditis. Experiments in Specific Aim 1 will define the role of pyroptosis in the heart during reovirus infection. Experiments in Specific Aim 2 will define mechanism by which reovirus induces pyroptosis using a combination in vivo infections in combination with primary cardiomyocytes. This research will have broad general impact by uncovering broad principles that govern immune mechanisms that contribute to viral cardiac disease.