Reiter's syndrome mechanism of chlamydial pathogenesis

描述（由申请人提供）：细菌病原体沙眼衣原体的生殖器感染与反应性关节炎（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性的，但沙眼原体启动和维持这一过程的方式仍有待阐明。这组和其他人的数据表明，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阶段被阻止。衣原体在体内表现出这些和其他不寻常的生物学特性，被认为处于持久状态。积累的数据进一步表明，持久性沙眼衣原体细胞以一种明显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久性的生物学，以及宿主和病原体在建立这种状态时相互作用的方式。在本文提出的研究中，我们使用具有良好特征的衣原体体外持久性模型，确定了沙眼衣原体中直接或间接参与建立和维持持久性状态的基因和基因集。我们还协调地定义了特异性、靶向宿主基因组的表达变化，作为在体外持久性模型中建立持久性衣原体感染的功能。这些分析的目标基因集将包括来自免疫系统、信号转导系统、能量转导系统等的基因集。总之，这些研究将不仅为持久性所需的衣原体蛋白提供重要的新见解，而且还将为以前未解决的沙眼衣原体与其原代宿主细胞之间的相互作用提供新见解。利用从这些研究中获得的信息，我们将确定在生殖器衣原体感染后进展为慢性疾病的患者与未进展为慢性疾病的患者之间差异的分子遗传学基础，并确定慢性衣原体诱导关节炎患者的缓解复发表型的分子基础。这些后一项研究将在疾病进展的各个阶段提供与宿主-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提供对ReA衣原体持久性和宿主-病原体相互作用的全面了解，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.