Type III exported effectors of Chlamydia trachomatis

描述（由申请人提供）：由于其流行率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的空泡内。毒力相关III型分泌系统（T3SS）的表达代表了用于调节关键宿主细胞途径的一种机制。在过去的资助周期中，我们确定了多种衣原体T3S底物能够影响这些宿主细胞过程。梭含有鉴定的效应蛋白CT694的沙眼衣原体基因座含有多种底物，所述底物在侵袭过程期间或之后被感染性颗粒部署。我们建议阐明这些蛋白质的抗宿主活性的分子机制，并描绘衣原体建立和维持一个专门的细胞内生态位的能力效应活性的后果。将采用旨在鉴定衣原体蛋白与宿主靶点相互作用的方法组合来建立相关功能。将在组织培养感染模型和急性衣原体感染的鼠模型中研究这些相互作用的后果。此外，我们建议评估是否在这些衣原体种属之间的差异，这些效应占任何不同的，种属特异性事件相关的衣原体早期发展。衣原体III型分泌系统代表了一种有吸引力的，但相对未开发的，实现宿主细胞活动的调节的机制。考虑到与专性细胞内细菌的研究相关的比较困难，III型分泌机制特异性靶向的宿主途径的研究继续代表了阐明新的致病机制的有效方法。这些研究将有助于加深对衣原体介导的疾病的理解，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.