Epigenetic regulation of innate immune responses to flaviviruses

 

Saguna2West Nile Virus (WNV) causes potentially lethal encephalitis in almost 1-2% of febrile patients. Inflammatory response initially triggered to clear WNV promotes additional damage resulting in neuronal death, however, the associated mechanisms are unclear. A potential approach for improving disease outcome focuses on regulating inflammatory processes induced by neurotropic viruses. The objective of this study is to characterize the role of histone deacetylases (HDACs) and histone acetyltransferases (HATs) in regulating WNV-induced inflammatory cytokines. Our overall hypothesis is that chromatin remodeling via changes in the HDACs and HATs activity is a critical step in the regulation of the host inflammatory response to WNV infection. In Aim 1 we will be determine the specific HDACs that respond to WNV infection in mouse bone marrow-derived macrophages (BMDMs) and Aim 2 will utilize a pharmacological and genetic approach to block specific HDACs by using HDAC inhibitors and siRNA and evaluate the production of multiple Th1/Th2 cytokines following WNV infection in BMDMs. Together these studies will provide mechanism-based evidence for the role of specific HDACs in WNV-associated inflammation and may identify novel targets for new generation therapeutics for patients infected with WNV.