Characterization of the Coxiella Dot/lcm homologues

Coxiella Dot/lcm 同源物的表征

• 批准号: 6868317
• 负责人: Joseph P Vogel
• 金额: $ 26.78万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868317
• 关键词: Coxiella burnetii; Legionella; bacterial genetics; bacterial proteins; biochemical evolution; biological models; gene mutation; genetic screening; laboratory rabbit; microorganism reproduction; virulence; yeast two hybrid 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.

描述（由申请人提供）： 贝氏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（查询热）。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形式。由于其高水平的传染性（单个微生物可能导致疾病），当它被雾化时具有传染性的能力，以及对恶劣环境条件的极端抵抗力，C。贝氏菌显示出潜在的生物战剂所必需的性质。更好地了解这种微生物如何引起疾病应该提供关于如何防止其滥用的信息。C.贝氏菌是一种专性细胞内病原体，其在溶酶体的不利环境中奇怪地复制，溶酶体是一种通常具有极强杀菌性的隔室。允许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。这种缺乏进展的主要原因是由于C。贝氏菌不能在没有真核宿主细胞的情况下培养，从而限制了传统的遗传分析。最近完成的C. Burnetii基因组计划。通过对C.通过对贝氏杆菌基因组中可能的毒力因子的研究，发现它含有相关病原体嗜肺军团菌使用的分泌系统的同源物。类似于C.伯内特湖嗜肺菌在宿主细胞内复制，尽管它在与溶酶体融合之前在修饰的液泡中开始其复制周期。L.嗜肺菌使用其由dot/icm基因编码的特化分泌系统将许多毒力因子输出到巨噬细胞中，以改变内吞途径。值得注意的是C。burnetii含有26种已知L. pneumophila Dot/Icm蛋白。我们建议确定C.贝氏菌Dot/Icm同源物是该病原体在宿主细胞内复制和鉴定由该系统分泌的蛋白质所必需的。