Herpes simplex virus (HSV) is a human pathogen which infects the epithelial cells of the mucosal tissues, leading to productive infection. Following primary replication the virus invades the sensory neurons to establish latency. Reactivation from latency occurs periodically, which is a lifelong source of virus responsible for recurrent infections. Therefore, a central issue in HSV biology is how HSV switches between lytic and latent cycles. Although transcriptional regulation of viral gene expression plays a crucial role little is known about other means of control, in particular innate immunity. Emerging evidence suggests that human is predisposed to HSV encephalitis when a mutation occurs in TANK-binding kinase 1(TBK1), which is a key component of Toll-like receptor dependent and independent pathways. This research will explore the hypothesis that TBK1-mediated innate immunity regulates HSV replication, spread, latency or reactivation. Upon activation TBK1 mediates the expression of type I IFN and inflammatory cytokines. Moreover, TBK1 promotes autophagy. In this process, TBK1 interacts with an array of host adaptor proteins, possibly in a signal specific manner. Thus, studies will be carried out to investigate the mechanisms of TBK1 regulation in response to HSV infection. The focus is the molecular nature of TBK1 that governs HSV infection in epithelial and neuronal cells. Furthermore, genetic studies will be performed to evaluate the impact of TBK1 on viral replication, penetrate, latency and reactivation. In parallel, analysis will be integrated to determine the IFN response and autophagy. Collectively, these studies will provide an insight into innate immune regulation of HSV persistency and pathogenesis.
NIH ExPorter
NIH ExPorter