Mechanism of TolC in the virulence of Francisella tularensis

 描述(申请人提供)：图拉氏方济氏菌是人畜共患病图拉热症的病原体。图拉氏杆菌是一种高毒力的细胞内病原体，当被雾化时很容易传播给人类，因此有可能被用作生物恐怖主义因子。图拉氏肺吸虫高感染性和致病力的分子基础尚不清楚。我们已经确定TolC对图拉氏丝虫的毒力至关重要。TolC是一种外膜通道蛋白，通过I型蛋白分泌途径参与多药外排和毒力因子的分泌。我们有证据表明，通过TolC分泌的效应蛋白具有抑制感染期间宿主细胞死亡反应的功能。这为细菌在受保护的细胞内生态位内复制提供了更长的时间，并延长了在宿主组织中的生存时间，从而使宿主-病原体的平衡变得有利于病原体。这些与TolC功能相关的寄主抑制活动可能是成功的细胞内生活方式和极强毒力的关键。这一建议将对TolC在弗朗西斯氏菌致病机制中的作用产生重要的新信息。该提案的第一个目的将定义TolC对人类致病性图拉氏杆菌Schu S4菌株毒力的贡献。该提案的第二个目标将使用补充方法来识别通过TolC分泌的毒力因子。这一建议不仅将使人们更好地了解图拉氏丝虫的毒力机制，而且还将为细胞内病原体在宿主中生存并导致疾病的机制提供见解。

 DESCRIPTION (provided by applicant): Francisella tularensis is the causative agent of the zoonotic disease tularemia. F. tularensis is a highly virulent intracellular pathogen that is easil transmitted to humans when aerosolized and thus has the potential for use as a bioterrorism agent. The molecular basis for the high infectivity and virulence of F. tularensis is not well understood. We have identified TolC as critical for the virulence of F. tularensis. TolC is an oute membrane channel protein involved in both multidrug efflux and the secretion of virulence factors by the type I protein secretion pathway. We have evidence that effector proteins secreted via TolC function to dampen host cell death responses during infection. This provides the bacteria extended time to replicate within the protected intracellular niche and prolongs survival within host tissues, thereby tipping the host-pathogen balance in favor of the pathogen. These host suppressive activities related to TolC function are likely key to the successful intracellular lifestyle and extreme virulence of F. tularensis. This proposal will generate critica new information about the mechanism of TolC in Francisella pathogenesis. The first aim of the proposal will define the contributions of TolC to the virulence of the human pathogenic F. tularensis Schu S4 strain. The second aim of the proposal will use complementary approaches to identify the virulence factors secreted via TolC. This proposal will not only lead to better knowledge of F. tularensis virulence mechanisms, but will also provide insights into mechanisms by which intracellular pathogens survive in the host and cause disease.