The role of TLR3 signaling in Chlamydia caused urogenital pathology

描述（由申请方提供）：衣原体感染引起的生殖道病理是女性生殖道内免疫反应的结果。先天性和适应性免疫应答都是作为宿主防御感染的一部分而被诱导的，并且特异性细胞因子和趋化因子在调节这些防御机制中起作用。由于上皮细胞是生殖道感染中衣原体感染的主要细胞类型，我们研究的总体目标是了解感染上皮细胞对宿主防御的贡献。我们发现输卵管上皮（OE）细胞中IFN-γ的合成主要以TLR 3依赖的方式发生。初步数据显示，来自TLR 3缺陷小鼠的OE细胞在合成参与先天性炎症反应的多种炎性细胞因子和趋化因子方面存在缺陷。比较野生型和TLR 3缺陷小鼠之间衣原体感染的发病机制的初步实验表明，TLR 3激发针对衣原体诱导的生殖道病理的保护性免疫应答。新的观察结果显示，某些炎性细胞因子和趋化因子在TLR 3缺陷小鼠中的合成减少，提出了这样的假设，即TLR 3调节这些炎性介质的合成，这有助于其在衣原体感染期间对宿主免疫应答的积极影响。我们的研究计划将涉及进一步检查体内的贡献TLR 3衣原体疾病进一步测试我们的假设，即小鼠缺乏TLR 3缺陷小鼠将有显着差异，在生殖道病理。我们建议首先鉴定生殖道 通过大体和显微组织学检查、淋巴细胞浸润、炎性介质合成，然后确定感染期间TLR 3信号传导对小鼠生殖道中细菌复制的影响，来比较野生型与TLR 3缺陷型的病理学。我们接下来提出确定IFN-γ在C.使用相同的方法，我们将确定TLR 3依赖的机制，有助于生殖病理学，不需要IFN-γ的合成。最后，我们建议使用TLR 3特异性细胞测定来鉴定作为PAMP用于体外TLR 3刺激的衣原体感染的组分。

DESCRIPTION (provided by applicant): 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.