(provided by The long term goal of this research proposal is to determine the mechanisms by which different signal transduction pathways lead to Interferon (IFN) induction in response to infections with DNA and RNA viruses. To combat viral infections most nucleated vertebrate cells are able to produce cytokines known as type I IFNs, which signal through the type I IFN receptor (IFNAR1), leading to activation of the JAK/STAT pathway and subsequent induction of a large set of genes important in antiviral responses. On the other hand, as a result of co-evolution, many viruses have developed strategies to inhibit the ability of host cells to either produce or respond to IFN. To understand how this network of host/pathogen interactions leads to disease, we need to define specific IFN induction pathways. Together with other groups, we have previously demonstrated that Toll-Like Receptors (TLRs) can mediate IFN production and antiviral responses through activation of IFN regulatory factors IRF3 and IRF7. Recent studies have also uncovered RIG-I like receptor (RLR) family members as intracellular nucleic acid sensors that can detect viral RNA sequences;however, the receptors responsible for recognizing intracellular viral DNA still remain to be determined. Research in our laboratory has been focused on identifying the intermediate signaling components and pathways that link different pattern recognition receptors, like TLRs and RLRs, to the common IRF3/7-dependent IFN induction in host innate immune responses against viral infections. Surprisingly, we have found that while TNF receptor associated factor 3 (TRAF3) deficient cells are defective in IFN induction in response to RNA viral infections, they produce elevated levels of IFN in response to DNA viral infections. The goal of this application is to gain a functional and mechanistic understanding of critical signaling molecules such as TRAF3 in host biodefense against DNA and RNA viral infections. We propose experiments to understand how TRAF3 has opposite functions in regulating RNA versus DNA induced type I interferon inductions. We will determine the mechanism responsible for and potential application of enhancing interferon production against DNA viral infection by activation of the non-canonical NF-kB activation pathway. We will also define the role and specificity of a new RIG-I like DEAD box containing DNA sensor and dissect its mediated type I interferon induction pathway in host response to DNA viruses.
The long term goal of this research proposal is to determine the mechanisms for diseases associated with viral infections and our host defense against viral infections. This proposal is focused on a particular molecule that can play an opposite role in regulating host immune response to DNA and RNA viruses. We will also develop novel therapeutic agents to treat disease models associated with DNA virus infections such as genital herpes.
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