Mechanism of TolC in the virulence of Francisella tularensis

 描述（由申请方提供）：土拉热弗朗西丝菌是人畜共患病土拉菌病的病原体。F.土拉热菌是一种高度致命的细胞内病原体，当其雾化时，可迅速传播给人类，因此具有用作生物恐怖剂的潜力。阐明了F.土拉热还没有得到很好的理解。我们已经确定TolC是F.土拉热。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分泌的效应蛋白在感染过程中抑制宿主细胞死亡反应。这为细菌提供了延长的时间来在受保护的细胞内生态位内复制并在宿主组织内存活，从而使宿主-病原体平衡倾向于病原体。这些与TolC功能相关的宿主抑制活性可能是F.土拉热。这一建议将产生关键的新信息的机制，TolC在弗朗西斯菌发病。该提案的第一个目的是确定TolC对人类致病性F.土拉菌S4菌株该提案的第二个目标将使用互补方法来鉴定通过TolC分泌的毒力因子。这一建议不仅将导致更好地了解F。土拉菌毒力机制，但也将提供深入了解细胞内病原体在宿主中生存和引起疾病的机制。

 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.