Modulation of Host Cell Functions by Coxiella burnetii

贝氏柯克斯体是一种专性胞内病原体， 与溶酶体融合而形成的液泡。柯克斯体蛋白参与 在产生这种独特的区室和调节宿主细胞功能中， 未知已经提出a考克斯/e/a编码的IVB型蛋白分泌 系统参与宿主发病机制。Coxiella型IVB系统在功能上是 与胞内病原体军团菌中发现的Dot/lcm系统相关 嗜肺菌这两种细菌IV型分泌系统之间的相似性 已被用于鉴定易位到真核生物中的柯克斯体蛋白质 通过Legionella Dot/lcm系统鉴定宿主细胞。Coxiella蛋白被鉴定为 Dot/LCM系统的底物都含有多个锚定重复序列结构域， 是在许多真核蛋白质中发现的蛋白质-蛋白质相互作用结构域。的 待检验的假设是这些CoxiellaAnk蛋白是Dot/1cm底物 在Coxiella感染期间转移到宿主细胞中，并且这些Ank蛋白是 直接参与调节宿主细胞功能。检查本地化Ank 感染柯克斯体的细胞中的蛋白质将测试这些蛋白质是否 易位了Ank蛋白在真核宿主细胞中的异位产生将揭示 受Ank蛋白影响的宿主进程。Ank蛋白的细胞靶点 将确定Coxiella Dot/lcm系统的其他底物， 通过遗传和分子方法鉴定。这些研究将阐明 致病决定因素，允许宿主细胞感染柯克斯体，并揭示 这种重要病原体所采用的细胞内感染策略。

Coxiella burnetii is an obligate intracellular pathogen that grows within a specialized vacuole that is derived from fusion with lysosomes. Coxiella proteins that participate in the creation of this unique compartment and that modulate host cell functions are unknown. It has been proposed that a Cox/e//a-encoded type IVB protein secretion system is involved in host pathogenesis. The Coxiella type IVB system is functionally related to the Dot/lcm system found in the intracellular pathogen Legionella pneumophila. The similarity between these two bacterial type IV secretion systems has been exploited to identify Coxiella proteins that are translocated into eukaryotic host cells by the Legionella Dot/lcm system. The Coxiella proteins identified as substrates of the Dot/lcm system all contain multiple ankyrin-repeat domains, which are protein-protein interaction domains found in many eukaryotic proteins. The hypothesis to be tested is that these Coxiella Ank proteins are Dot/lcm substrates translocated into host cells during Coxiella infection and that these Ank proteins are directly involved in modulation of host cell functions. Examining the localization Ank proteins in cells infected with Coxiella will test whether these proteins are translocated. Ectopic production of Ank proteins in eukaryotic host cells will reveal host processes that are affected by Ank proteins. Cellular targets for the Ank proteins will be determined and additional substrates of the Coxiella Dot/lcm system will be identified using genetic and molecular approaches. These studies will elucidate pathogenic determinants that allow host cell infection by Coxiella and reveal intracellular infection strategies employed by this important pathogen.