Characterization of the Coxiella Dot/lcm homologues

描述（由申请人提供）： 伯纳特柯克斯体是一种革兰氏阴性细菌，可引起人畜共患疾病 Q 热（查询发烧）。这种疾病可能危及生命，范围从急性流感样疾病到经常表现为心内膜炎的慢性疾病。 Due to its high level of infectivity (a single organism may cause disease), its ability to be infectious when it is aerosolized, and its extreme resistance to harsh environmental conditions, C. burnetii displays the properties necessary for a potential biowarfare agent.更好地了解这种生物体如何引起疾病应该提供有关如何防止其滥用的信息。 C. burnetii is an obligate intracellular pathogen that curiously replicates inside the hostile environment of a lysosome, a compartment that is normally exceedingly bactericidal.使这种生物体在溶酶体内生存、在宿主细胞内复制并引起疾病的因素尚未确定。 The major reason for this lack of progress is due to the fact that C. burnetii cannot be cultured in the absence of eukaryotic host cells, thereby limiting traditional genetic analysis.最近完成的 C.burnetii 基因组计划提供了一种替代方法。 By examining the C. burnetii genome for possible virulence factors, it was discovered that it contains homologues to a secretion system used by the related pathogen Legionella pneumophila. Similar to C. burnetii, L. pneumophila replicates inside host cells although it begins its replicative cycle in a modified vacuole prior to fusing with lysosomes. L. pneumophila uses its specialized secretion system, encoded by the dot/icm genes, to export a number of virulence factors into macrophages in order to alter the endocytic pathway.值得注意的是，伯内特衣原体含有 26 种已知嗜肺军团菌 Dot/Icm 蛋白中 23 种的同源物。 We propose to determine if the C. burnetii Dot/Icm homologues are needed for this pathogen to replicate inside host cells and to identify proteins secreted by this system.

DESCRIPTION (provided by applicant): Coxiella burnetii is a Gram negative bacterium that causes the zoonotic illness Q fever (for query fever). This disease can be life-threatening and ranges from an acute, flu-like illness to a chronic form of that frequently presents as endocarditis. Due to its high level of infectivity (a single organism may cause disease), its ability to be infectious when it is aerosolized, and its extreme resistance to harsh environmental conditions, C. burnetii displays the properties necessary for a potential biowarfare agent. A better understanding of how this organism causes disease should provide information on how to defend against its misuse. C. burnetii is an obligate intracellular pathogen that curiously replicates inside the hostile environment of a lysosome, a compartment that is normally exceedingly bactericidal. The factors that allow this organism to survive inside lysosomes, replicate inside host cells, and cause disease have not been identified. The major reason for this lack of progress is due to the fact that C. burnetii cannot be cultured in the absence of eukaryotic host cells, thereby limiting traditional genetic analysis. An alternative approach has been provided by the recent completion of the C. burnetii genome project. By examining the C. burnetii genome for possible virulence factors, it was discovered that it contains homologues to a secretion system used by the related pathogen Legionella pneumophila. Similar to C. burnetii, L. pneumophila replicates inside host cells although it begins its replicative cycle in a modified vacuole prior to fusing with lysosomes. L. pneumophila uses its specialized secretion system, encoded by the dot/icm genes, to export a number of virulence factors into macrophages in order to alter the endocytic pathway. Remarkably C. burnetii contains homologues to 23 of the 26 known L. pneumophila Dot/Icm proteins. We propose to determine if the C. burnetii Dot/Icm homologues are needed for this pathogen to replicate inside host cells and to identify proteins secreted by this system.