The role of TLR3 signaling in Chlamydia caused urogenital pathology

TLR3信号在衣原体引起的泌尿生殖病理中的作用

基本信息

批准号：
9117379
负责人：
WILBERT A DERBIGNY
金额：
$ 38.51万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9117379
关键词：
Adaptor Signaling Protein Bacteria Bacterial Infections Binding Biological Assay Biological Models Cell Line Cell surface Cells Cellular Assay Chlamydia Chlamydia Infections Chlamydia trachomatis Chronic Cicatrix Data Defense Mechanisms Disease Disease Progression Double-Stranded RNA Epithelial Cells Epithelium Female Foundations Gene Expression Genetic Transcription Genitourinary system Goals Health Host Defense Human Immune Immune response Immunity In Vitro Infection Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interferons Interleukin-1 Investigation Knockout Mice Lead Lymphocyte Mammalian Oviducts Measures Methodology Microscopic Modeling Molecular Mus Outcome Pathogenesis Pathology Pattern Pattern recognition receptor Pelvic Inflammatory Disease Play Process Production Qualifying Research Role Sexually Transmitted Diseases Signal Pathway Signal Transduction TLR3 gene Testing Therapeutic Toll-like receptors Trauma Vaccines Virus Diseases Wild Type Mouse adaptive immunity base cell type chemokine cytokine design in vivo insight microbial mouse model novel oviduct scarring pathogen prevent receptor reproductive reproductive tract research study response therapeutic development tool vaccine development

项目摘要

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.

描述（由适用提供）：衣原体感染引起的生殖道病理学是女性生殖道中免疫复杂的结果。先天性和适应性免疫回报都是作为宿主防御感染的一部分而诱导的，特定的细胞因子和趋化因子在确定这些防御机制方面发挥了作用。由于上皮细胞是生殖道感染过程中被衣原体有效感染的主要细胞类型，因此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。我们表明，输卵管上皮（OE）细胞中的IFN-合成以TLR3依赖性方式出现。初步数据表明，源自TLR3缺陷型小鼠的OE细胞在合成众多炎性细胞因子和趋化因子的合成中有缺陷。比较野生型和TLR3缺乏小鼠之间衣原体感染的发病机理的试验实验表明，TLR3引起了针对衣原体诱导的生殖器诱导的诱导的受保护的免疫响应。新的观察结果表明，TLR3缺陷小鼠中某些炎症细胞因子和趋化因子的合成减少，它提出了这样的假设，即TLR3调节这些炎症介质的合成，从而有助于其对衣原体感染期间对宿主免疫反应的积极影响。我们的研究计划将涉及进一步研究TLR3对衣原体疾病的体内贡献，进一步检验我们的假设，即缺乏TLR3缺乏小鼠的小鼠在生殖道病理学上将有显着差异。我们建议最初鉴定生殖道通过总体和微观组织学检查，淋巴细胞浸润，炎症介质的合成，然后确定TLR3信号传导在感染期间小鼠生殖段中具有细菌复制的作用。我们下一个建议使用相同的方法确定ifn-在穆里达鲁姆感染的发病机理中的作用，我们将确定有助于不需要IFN-合成的生殖病理学的TLR3依赖机制。最后，我们建议使用TLR3特异性的细胞测定法确定衣原体感染的成分，该成分在体外用作TLR3刺激的症状。