Host Factors in Susceptibility to Chlamydial Disease

描述（由申请方提供）：沙眼衣原体感染是 在美国最常报告的传染病诊断， 衣原体疾病的治疗和后遗症， 年仅在美国。妇女感染往往没有症状。 宿主免疫反应的变化可能是造成不良后果的原因 因为并非所有感染者都会长期受到感染， 疾病的后果。在那些进展到疾病的人中， 组织的结构和功能会因一个过程而发生显著改变 最终导致疤痕和输卵管堵塞。这 导致输卵管因素不孕和异位妊娠的风险。我们 一种假设是，那些维持这种结果的人有因素失调 负责细胞外基质的修复。解决 假设，我们将使用衣原体疾病的小鼠模型， 存在已被表征为抗性或敏感的菌株， 由输卵管损伤和不孕的结果表明。在方法上，我们将 首先广泛比较和对比这些菌株， 修改和修复泌尿生殖道细胞外基质的能力 在体内和体外。随后，我们将定义矩阵的作用 金属蛋白酶（MMPs）在衣原体疾病结局中的体内研究 研究中，酶被抑制， 影响其活性和生产。我们将定义一个 特定金属蛋白酶对疾病过程的作用， 编码酶的基因缺失的小鼠。最后，贡献 特异性炎症细胞对细胞外基质的调节， 衣原体疾病将通过骨髓嵌合体的产生来定义 敏感和耐药小鼠品系之间的差异以及随后的 白细胞群总之，本提案的目的是界定 宿主因素是造成衣原体疾病不良结局的原因。的 获得的信息将有助于开发治疗方法， 改善衣原体疾病过程;非侵入性诊断指标 进行性瘢痕形成和异常生理结果; 衣原体疾病高危人群的预后指标;以及， 在设计安全有效的衣原体疫苗方面取得进一步进展， 避免不良后果。

DESCRIPTION (provided by the applicant): Chlamydia trachomatis infections are the most commonly reported transmissible diseases in the U.S. Diagnosis, treatment, and sequelae of chlamydial disease cost billions of dollars each year in the U.S. alone. The infection is often asymptomatic in women. Variations in the host immune response are likely to blame for adverse outcomes because not all persons who become infected will suffer the long-term consequences of the disease. In those who progress to disease, the affected tissues are significantly altered in their structure and function by a process that ultimately results in scarring and blockage of the fallopian tubes. This results in tubal factor infertility and risk of ectopic pregnancy. Our hypothesis is that those who sustain this outcome have dysregulation of factors which are responsible for the repair of the extracellular matrix. To address hypothesis, we will use a mouse model of chlamydial disease where inbred strains exist which have been characterized as resistant or susceptible as indicated by the outcomes of tubal damage and infertility. In approach, we will first extensively compare and contrast these strains with regard to their ability to modify and repair the extracellular matrix of the urogenital tract in vivo and in vitro. Subsequently, we will define the role of matrix metalloproteinases (MMPs) in the outcome of chlamydial disease through in vivo studies where the enzymes are inhibited pharmacologically or cytokines that influence their activity and production are neutralized. We will then define a role of specific metalloproteinases to the disease process through the use of mice with deletions in genes that encode the enzymes. Lastly, the contribution of specific inflammatory cells to the modulation of extracellular matrix in chlamydial disease will be defined by the production of bone marrow chimeras between susceptible and resistant strains of mice and subsequent depletions of leukocyte populations. In summary, it is the intent of this proposal to define host factors that are responsible for adverse chlamydial disease outcome. The information derived will assist in the development of therapies which could ameliorate the chlamydial disease process; noninvasive diagnostic indicators of progressive scarring and abnormal physiological outcome; development of prognostic indicators of those at high risk for chlamydial disease; and, further advances in design of a safe and effective chlamydial vaccine through avoidance of adverse outcomes.