Host Factors in Susceptibility to Chlamydial Disease

描述(申请人提供)：沙眼衣原体感染 在美国最常见的传染病诊断报告中， 衣原体病的治疗和后遗症每人花费数十亿美元 仅在美国就有一年。这种感染在女性中通常是无症状的。 宿主免疫反应的变化可能是造成不良后果的原因。 因为并不是所有感染者都会长期遭受 疾病的后果。在那些进展为疾病的人中，受影响的 通过一个过程，组织的结构和功能发生了显著的变化 这最终会导致输卵管结疤和堵塞。这 结果导致输卵管因素不孕和异位妊娠的风险。我们的 假说是，那些维持这种结果的人有因素的失调 它们负责细胞外基质的修复。致信地址 假设，我们将使用近亲繁殖的衣原体病小鼠模型 存在已被表征为耐药或敏感的菌株 表现为输卵管损伤和不孕症。在方法上，我们将 首先，对这些菌株进行广泛的比较和对比 修饰和修复泌尿生殖道细胞外基质的能力 在体内和体外。随后，我们将定义矩阵的角色 金属蛋白酶(MMPs)与衣原体疾病体内转归的关系 酶被药物抑制或细胞因子被抑制的研究 影响他们的活动和生产被中和。然后，我们将定义一个 特异性金属蛋白酶在疾病过程中的作用 编码这些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控作用 衣原体疾病将通过产生骨髓嵌合体来定义 在敏感和耐药品系的小鼠和随后耗尽的 白细胞群。总而言之，本提案的目的是定义 导致衣原体疾病不良结局的宿主因素。这个 所获得的信息将有助于开发治疗方法， 改善衣原体疾病进程；非侵入性诊断指标 进行性疤痕形成和异常生理结局；发展 衣原体疾病高危人群的预后指标；以及 一种安全有效的衣原体疫苗设计的进一步进展 避免不良后果的发生。

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.