Grant: Project Grant

Type I interferon plays a critical role in promoting host survival during viral infections. However, immediately following viral infections hosts become susceptible to opportunistic bacterial infections, a phenomenon known as "superinfection". Type I interferon has been considered as the suspect. We have previously reported that type I interferon signaling promotes host fatality in a mouse typhoid model, although the mechanism through which type I interferon signaling leads to host susceptibility is not clear. In this proposal we provide preliminary results which show that type I interferon signaling compromises the expansion of myeloid cells which are the frontline cells of the immune system that are required for protection. We show that interferon signaling induces inhibition of the fitness of macrophages by reducing the expression of genes that mediate defense against the toxic reactive oxygen species. We further show that type I interferon induces the expression of an endogenous inhibitor of serine proteases which intrinsically impairs the ability of macrophages to control the proliferation of intracellular bacteria. We are proposing three aims to test the roles of genes and pathways mentioned above in regulating host susceptibility in the murine typhoid model. We will use multidisciplinary approaches to evaluate the mechanisms involved.