Reiter's syndrome mechanism of chlamydial pathogenesis

描述(由申请人提供)：生殖器感染沙眼衣原体与反应性关节炎(REA)的发展有关。虽然很明显，导致关节疾病的过程在本质上部分是免疫致病的，但沙眼衣原体启动和维持这一过程的方式仍有待阐明。来自该小组和其他小组的数据表明，滑膜衣原体表现出不寻常的代谢和转录特征，并在发育周期的后期停止。在体内表现出这些和其他不寻常的生物属性的衣原体被指定为持续状态。积累的数据进一步表明，持久性沙眼衣原体细胞以一种公开但鲜为人知的方式与宿主细胞相互作用。开发治疗衣原体相关REA的有效疗法的关键在于了解衣原体持续存在的生物学，以及在这种状态建立期间宿主和病原体相互作用的方式。在这里提出的研究中，我们定义了沙眼衣原体的基因和基因集，这些基因和基因集直接或间接地参与了沙眼衣原体持续状态的建立和维持，使用了一个特征良好的衣原体持续体外模型。我们还协调地将特定的、靶向的宿主基因组的表达变化定义为在体外持续性衣原体感染模型中建立的函数。这些分析的目标基因组将包括来自免疫系统、信号转导系统、能量转导系统和其他系统的基因。总之，这些研究将提供至关重要的新见解，不仅是对维持沙眼衣原体所需的衣原体蛋白的研究，也是对沙眼衣原体与其主要宿主细胞之间以前未解决的相互作用的研究。利用从这些研究中获得的信息，我们将确定进展为慢性病的患者与未患生殖器衣原体感染的患者之间差异的分子遗传学基础，并确定慢性衣原体引起的关节炎患者复发复发表型的分子基础。这些后一项研究将提供与疾病发展不同阶段的宿主-病原体相互作用有关的重要信息。综上所述，本文提出的研究结果将全面了解衣原体在REA中的持久性和宿主与病原体的相互作用，从而为设计和实施合理的治疗策略奠定基础。

DESCRIPTION (provided by applicant): Genital infection with the bacterial pathogen Chlamydia trachomatis is associated with development of reactive arthritis (ReA). While it is clear that the process leading to joint disease is partly immunopathogenic in nature, the means by which C trachomatis initiates and maintains that process remain to be elucidated. Data from this group and others have shown that synovial Chlamydiae display unusual metabolic and transcriptional characteristics and are arrested at a late stage of the developmental cycle. Chlamydiae displaying these and other unusual biologic attributes in vivo are designated to be in the persistent state. Accumulating data further indicate that persistent C. trachomatis cells interact in an overt but poorly understood manner with their host cells. The key to development of effective therapies to treat Chlamydia-associated ReA lies in understanding the biology of chlamydial persistence, and the means by which host and pathogen interact during establishment of that state. In the studies proposed here, we define the genes and gene sets from C. trachomatis that are involved directly or indirectly in establishment and maintenance of the persistent state, using a well-characterized in vitro model of chlamydial persistence. We also, and coordinately, define the changes in expression for specific, targeted sets of host genes as a function of establishment of persistent chlamydial infection in the in vitro model of persistence. The gene sets to be targeted in these analyses will include those from the immune system, the signal transduction system, the energy transduction system, and others. Together, these studies will provide critical new insight not only into chlamydial proteins required for persistence, but also into previously unaddressed interactions between C. trachomatis and its primary host cells. Using information gained from these studies, we will determine the molecular genetic basis for differences between patients who progress to chronic disease and those who do not following genital chlamydial infection, and we define the molecular basis for the remittingrelapsing phenotype of patients with chronic Chlamydia-induced arthritis, and. These latter studies will give important information relating to host-pathogen interaction during various stages of disease progression. Taken together, the results of the studies proposed here will provide a comprehensive understanding of chlamydial persistence and host-pathogen interaction in ReA and therefore will form the foundation for design and implementation of rational strategies to treat the disease.