In vivo regulation of Salmonella enterica serovar Typhi Vi polysaccharide and the consequences for the pathogenesis of the infection and induction of immune responses. (360G-Wellcome-081743_Z_06_Z)

Vi is a surface polysaccharide capsule expressed by pathogenic isolates of S.enterica serovar Typhi, Dublin and Paratyphi. Vi enhances pathogenicity by inhibiting bacterial internalization and killing by phagocytes but can also be detrimental to the bacteria due to interference with key stages of the infection and to elicitation of anti-Vi antibodies. Thus, careful regulation of Vi biosynthesis in different anatomical sites and at different times after infection would optimize both S. enterica i nfectivity and evasion of immune responses. Indeed, our preliminary work clearly indicates that Vi expression is regulated in vivo. The main objectives of the project are to: a) study the timing and anatomical location of Vi capsular polysaccharide expression in the tissues at the single cell level in an in vivo infection; b) determine whether and how Vi affects the interactions between S. enterica and phagocytic cells; c) manipulate Vi expression in live attenuated S. enterica strains to i nduce protective immune responses against infection. The work will provide crucial knowledge on the role of surface structures in the pathogenesis of typhoidal infections and will set the basis for eliciting immune responses against individual bacterial virulence determinants directed at the sites of infection where these are maximally expressed.