Reproductive tract pathology caused by Chlamydia infections are the result of the immune responses within the female reproductive tract. Both innate and adaptive immune responses are induced as part of the host defense against infection, and specific cytokines and chemokines play a role in regulating these defense mechanisms. Because epithelial cells are the major cell type productively infected with Chlamydia during genital tract infections, the overall goal of our research is to understand the contribution of the infected-epithelial cells to the host defense. We showed that IFN-? synthesis in oviduct epithelial (OE) cells occurred in a mostly TLR3-dependent manner. Preliminary data show that OE cells derived from TLR3- deficient mice were defective in the synthesis of a multitude of inflammatory cytokines and chemokines involved in the innate inflammatory response. Pilot experiments comparing the pathogenesis of Chlamydia infection between wild-type and TLR3-deficient mice show that TLR3 elicits a protective immune response against Chlamydia-induced genital-tract pathology. The novel observation showing diminished synthesis of certain inflammatory cytokines and chemokines in TLR3-deficient mice, presents the hypothesis that TLR3 regulates the synthesis of these inflammatory mediators which contributes to its positive impact on the host immune response during Chlamydia infection. Our research plan will involve further examining the in vivo contributions of TLR3 to Chlamydia disease by further testing our hypothesis that mice deficient in TLR3-deficient mice will have significant differences in reproductive tract pathology. We propose to initially qualify the reproductive tract pathology in wild-type versus TLR3-deficient via gross and microscopic histological examination, lymphocyte infiltration, inflammatory mediator synthesis, and then determining the effect that TLR3 signaling has bacterial replication in the reproductive tracts of the mice during infection. We next propose to ascertain the role of IFN-? specifically in the pathogenesis of C. muridarum infection using the identical methodologies, and we will identify the TLR3-dependent mechanisms that contribute to reproductive pathology that do not require IFN-? synthesis. Finally, we propose to identify the component of the Chlamydia infection that serves as the PAMP for TLR3 stimulation in vitro using a TLR3-specific cellular assay.