Modulation of Host Cell Functions by Coxiella burnetii

伯氏柯克斯体是一种专性细胞内病原体，生长在一种特殊的 与溶酶体融合而形成的液泡。参与的柯克斯体蛋白 在创建该独特隔室和调节宿主细胞功能时 未知。已有研究提出a-COX/e//a-编码型IVB蛋白分泌 系统参与了宿主的发病过程。Coxiela型IVB系统在功能上 与细胞内病原体军团菌中发现的Dot/LCM系统有关 嗜肺症。这两种IV型细菌分泌系统的相似性 已经被用来鉴定被转移到真核细胞中的柯克斯体蛋白 通过军团菌Dot/LCM系统寄主细胞。经鉴定的柯克斯体蛋白 Dot/LCM系统的底物都含有多个ankyrin-Repeat结构域，该结构域 是存在于许多真核蛋白质中的蛋白质-蛋白质相互作用结构域。这个 有待检验的假设是这些柯克斯体Ank蛋白是Dot/LCM底物 在柯克斯体感染期间转移到宿主细胞中，这些Ank蛋白是 直接参与宿主细胞功能的调节。检查本地化问题 感染柯克斯体的细胞中的蛋白质将测试这些蛋白质是否 移位了。在真核宿主细胞中异位生产Ank蛋白将揭示 受Ank蛋白影响的宿主过程。ANK蛋白的细胞靶点 将被确定，Coxiella Dot/LCM系统的附加底物将被确定 使用遗传和分子方法进行鉴定。这些研究将阐明 允许宿主细胞感染柯克斯体的致病决定因素 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.