Virulence Mechanisms of Salmonella Typhi

描述(由申请人提供)：伤寒沙门氏菌在人类中引起一种严重的系统性感染，称为伤寒，每年导致约60万人死亡。我们的长期目标是阐明伤寒发病的分子机制。这项应用的目的是研究伤寒沙门氏菌特异性毒力因子Vi衣壳抗原在宿主病原体相互作用中的作用机制。我们的中心假设是，Vi抗原的表达阻止了对病原体相关分子模式(PAMPs)子集的先天免疫识别，从而改变了与宿主细胞的相互作用。我们将测试我们假设的不同方面，并通过追求以下两个特定目标来实现此应用程序的目标。1.确定Vi囊膜抗原的表达是否能阻断已知伤寒沙门氏菌PAMPs的Toll样受体(TLR)识别。2.确定Vi抗原的表达是否影响伤寒沙门氏菌在人巨噬细胞中的吞噬、吞噬小体成熟和存活。这项拟议的工作具有创新性，因为它挑战了表达多糖胶囊主要是为了避免吞噬的教条。我们期望我们的方法将确定Vi抗原在伤寒期间逃避TLR识别中的作用。这一结果将是重要的，因为它有望在宿主病原体相互作用中建立一种新的范式，该范式可能适用于许多其他被囊化的病原体。

DESCRIPTION (provided by applicant): Salmonella enterica serotype Typhi causes a severe systemic infection in humans, termed typhoid fever, which is responsible for some 600,000 deaths annually. Our long-range goal is to elucidate the molecular mechanisms involved in the pathogenesis of typhoid fever. The objectives of this application are to study the mechanism by which a S. Typhi-specific virulence factor, the Vi capsular antigen, contributes to host pathogen interaction. Our central hypothesis is that expression of the Vi-antigen blocks innate immune recognition of a subset of pathogen associated molecular patterns (PAMPs), thereby altering interaction with host cells. We will test different aspects of our hypothesis and accomplish the objectives of this application by pursuing the following two specific aims. 1. Determine whether expression of the Vi capsular antigen can block Toll-like receptor (TLR) recognition of known S. Typhi PAMPs. 2. Determine whether expression of the Vi antigen affects phagocytosis, phagosome maturation and survival of S. Typhi in human macrophages. The proposed work is innovative because it challenges the dogma that expression of a polysaccharide capsule serves mainly to avoid phagocytosis. It is our expectation that our approach will establish the role of the Vi antigen in evasion of TLR recognition during typhoid fever. This outcome will be significant because it promises to establish a new paradigm in host pathogen interaction that may be applicable to a number of other capsulated pathogens.