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.<P> 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. <P> 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. <P> 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. <P> 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.