Role of TLR2 Signaling in Innate and Adaptive Responses to Chlamydiae

沙眼衣原体是全球细菌性性传播感染的主要原因， 每年相关费用超过20亿美元。在女性中，未经治疗的感染可能会发展为严重的 生殖道后遗症衣原体似乎不表达积极诱导疾病的蛋白质， 受感染宿主的组织损伤相反，衣原体感染后的病理是 这是侵略性宿主炎症反应的结果。利用C.小鼠模型，我们有 表明先天性病原体识别受体TLR 2对输卵管发育至关重要， 病理TLR 2基因敲除（KO）小鼠在衣原体感染后不发生输卵管病变。在 此外，质粒缺陷型C.在小鼠中引起正常强度和持续时间感染的鼠伤寒沙门氏菌 导致输卵管疾病而不刺激TLR 2。我们的数据表明，在TLR 2存在的情况下， 信号，衣原体感染激发比所需更大幅度的免疫应答， 随后导致组织病理学。在这个应用中，我们提出验证我们的新模型， 一种衣原体疾病，病理学是对原发性衣原体感染的反应， 以下途径：1）TLR 2介导的先天免疫细胞的过度活化，导致 超过细菌清除所需的量，最终促进过度的组织损伤， 瘢痕形成; 2）TLR 2介导的CD 4 T细胞应答的过度活化。此外，我们建议， 我们的研究超越了小鼠，通过研究衣原体诱导的TLR 2信号传导和相应的 人类生殖道组织的炎症反应。完成学业将使我们能够 确定：（1）衣原体诱导的TLR 2依赖性信号传导对小鼠天然免疫细胞的影响 体外和体内活化，（2）小鼠T细胞应答和解决活化的机制。 衣原体感染不产生输卵管组织损害，（3）衣原体诱导的输卵管组织损害 TLR 2激活对人类生殖道组织炎症反应的影响

Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections worldwide, with annual related costs exceeding $2 billion. In women, untreated infections may progress to serious reproductive tract sequela. Chlamydiae to not appear to express proteins that actively induce disease or tissue damage in the infected host. Rather, the pathology that follows chlamydial infection is the consequence of an aggressive host inflammatory response. Using the C. muridarum mouse model, we have shown that the innate pathogen recognition receptor, TLR2, is essential for development of oviduct pathology. TLR2 gene knock-out (KO) mice do not develop oviduct pathology after chlamydial infection. In addition, plasmid-deficient C. muridarum that cause an infection in mice of normal intensity and duration fail to cause oviduct disease and do not stimulate TLR2. Our data indicate that in the presence of TLR2 signaling, chlamydial infection elicits an immune response of greater magnitude than what is needed and subsequently leads to tissue pathology. In this application we propose to validate our novel model of chlamydial disease where pathology occurs in response to primary chlamydial infection by one or both of the following paths: 1) TLR2-mediated hyper-activation of innate immune cells leading to a response that exceeds what is required for bacterial clearance, ultimately promoting excessive tissue damage and scarring; 2) TLR2-mediated hyper-activation of the CD4 T cell response. In addition, we propose to advance our studies beyond the mouse by investigating chlamydial-induced TLR2 signaling and consequential inflammatory responses in human reproductive tract tissues. Completion of our studies will allow us to determine: (1) the effect of chlamydia-induced TLR2-dependent signaling on murine innate immune cell activation in vitro and in vivo, (2) the mechanism by which mouse T cells respond to and resolve a Chlamydia infection without producing oviduct tissue damage, (3) the contribution of chlamydia-induced TLR2 activation to the inflammatory response of human reproductive tract tissue.