Reovirus induction of host inflammatory responses

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.

Grant Number: 5R21AI178222-02
NIH Institute/Center: NIH
Principal Investigator: Karl Boehme