Virulence Mechanisms of Salmonella Typhi

描述（由申请方提供）：伤寒沙门氏菌血清型引起人类严重的全身性感染，称为伤寒，每年造成约600，000人死亡。我们的长期目标是阐明伤寒发病机制的分子机制。本申请的目的是研究S.伤寒特异性毒力因子，Vi荚膜抗原，有助于宿主病原体相互作用。我们的中心假设是Vi-抗原的表达阻断病原体相关分子模式（PAMP）的子集的先天免疫识别，从而改变与宿主细胞的相互作用。我们将测试我们的假设的不同方面，并通过追求以下两个具体目标来实现本申请的目标。1.确定Vi荚膜抗原的表达是否可以阻断已知S.伤寒PAMP。2.确定Vi抗原的表达是否影响S.人类巨噬细胞中的伤寒。拟议的工作是创新的，因为它挑战的教条，表达的多糖胶囊主要是为了避免吞噬作用。我们的期望是，我们的方法将确定伤寒期间Vi抗原在逃避TLR识别中的作用。这一结果将是重要的，因为它有望建立一个新的范例，在宿主病原体的相互作用，可能适用于其他一些胶囊病原体。

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.