Type III exported effectors of Chlamydia trachomatis

描述（由申请人提供）：由于沙眼衣原体的流行以及急性和慢性疾病对健康和社会经济的综合影响，人类病原体沙眼衣原体在美国是一个重要的问题。衣原体是专性细胞内病原体，具有调节宿主细胞功能的能力，同时被隔离在膜结合液泡内。毒力相关的III型分泌系统（T3SS）的表达代表了调节关键宿主细胞通路的一种机制。在过去的资助周期中，我们发现了多种能够影响这些宿主细胞过程的衣原体T3S底物。沙眼衣原体基因座含有已鉴定的效应蛋白CT694，它含有多种底物，这些底物在入侵过程中或随后被感染颗粒部署。我们建议阐明这些蛋白抗宿主活性的分子机制，并描述效应活性对衣原体建立和维持细胞内特殊生态位的能力的影响。设计用于鉴定衣原体蛋白与宿主靶标相互作用的方法组合将用于建立相关功能。这些相互作用的后果将在组织培养感染模型和急性衣原体感染的小鼠模型中进行研究。我们进一步建议评估衣原体物种之间这些效应物的差异是否解释了与早期衣原体发育相关的任何独特的物种特异性事件。衣原体III型分泌系统代表了一个有吸引力的，但相对未被探索的机制，以实现宿主细胞活性的调节。鉴于专性细胞内细菌的研究相对困难，研究III型分泌机制特异性靶向的宿主途径仍然是阐明新的致病机制的有效方法。这些研究将增进对衣原体介导的疾病的了解，并有可能产生新的预防和治疗方法。

DESCRIPTION (provided by applicant): The human pathogen Chlamydia trachomatis is a significant concern in the United States due to its prevalence and the combined health and socioeconomic impact of acute and chronic disease. Chlamydiae are obligate intracellular pathogens and possess the ability to modulate host-cell functions while sequestered within a membrane-bound vacuole. Expression of a virulence-associated type III secretion system (T3SS) represents one mechanism employed to modulate critical host cell pathways. During the past funding cycle, we identified multiple chlamydial T3S substrates capable of influencing these host cellular processes. The C. trachomatis locus containing the identified effector protein CT694 contains multiple substrates that are deployed by infectious particles during or subsequent to the invasion process. We propose to elucidate molecular mechanisms regarding the anti-host activities of these proteins and delineate the consequences of effector activity on the ability of Chlamydiae to establish and maintain a specialized intracellular niche. A combination of methods designed to identify interactions of chlamydial proteins with host targets will be employed to establish relevant functions. The consequences of these interactions will be investigated in both a tissue culture infection model and a murine model of acute chlamydial infection. We furthermore propose to evaluate whether differences in these effectors among chlamydial species account for any of the distinct, species-specific events related to early chlamydial development. The chlamydial type III secretion system represents an attractive, yet relatively unexplored, mechanism to achieve modulation of host cell activities. Given the comparative difficulty associated with study of obligate intracellular bacteria, investigation of host pathways specifically targeted by the type III secretion mechanism continues to represent a productive approach to elucidate novel pathogenic mechanisms. These studies will lead to an enhanced understanding of Chlamydia-mediated disease and have the potential to yield novel preventative and treatment therapies. PUBLIC HEALTH RELEVANCE: Chlamydia trachomatis, an agent of sexually transmitted disease, relies on a specialized secretion mechanism to deploy proteins exerting anti-host activities essential to pathogenesis. This application contains work designed to identify these anti-host proteins and determine their specific contributions to chlamydial disease.