The discovery of the Toll-Like Receptor Proteins (TLRs) and their importance in the regulation of host response to infection has led to a series of investigations related to the role of host proteins and cytokines in microbial pathogenesis. Recent work has demonstrated that not only do these TLRs function as cell surface receptors for foreign antigens, but also that TLRs (especially TLR 3, 7, 8 and 9) are endosomally localized and they recognize infectious agents (particularly viruses and viral nucleic acids). In addition to the TLRs, the production of type 1 interferons (IFNs) has been shown to be regulated by cytoplasmic RNA helicase proteins, like RIG-I and Mda-5, and by inflammosame proteins like NLRP-3 (or NALP-3, Cryopyrin) which are related to the NOD family of proteins. Several Interferon Regulatory Factors (IRFs), which control the production of type I IFNs, have been implicated downstream of these different viral sensing pathways. The overall hypothesis of the Project is that pattern recognition proteins respond to particular viral antigens and that those responses are regulated by other viral proteins and it is the effect of the host cytokines induced as a result of this interaction that determines the pathogenic potential of a virus. Project 1 (Kurt-Jones) will define the role of TLRs in HSV induced inflammatory responses and viral pathogenesis and how IRF-1 signaling regulates these responses. Project 2 (Fitzgerald) will define the role of IL-I, NLRP-3, and TLR-independent DNA sensors in the virus-induced production of inflammatory cytokines and type I interferons, and the control of anti-viral immunity. Project 3 (Knipe) will define how certain viral proteins regulate TLR signaling and TLR adapters (and other pattern recognition proteins) and affect the secretion of interferon and cytokines. Project 4 (Finberg) will examine how recently defined polymorphisms in TLRs and other host genes important in innate immunity, affect reactivation of HSV. All Projects involve the use of common reagents and the definition of new paradigms related to recognition and response of the host to HSV.