Characterization of the Coxiella Dot/lcm homologues

点击翻译按钮获取中文摘要

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.