Salmonellae cause either acute gastroenteritis or the systemic febrile illness typhoid in humans. Both syndromes are significant public health problems worldwide. The interactions between Salmonella and mammalian cells that result in invasion and intracellular growth of the bacteria depend on both bacterial and host factors. Metal ions such as iron, magnesium and manganese play important roles in these interactions. Mutations in bacterial proteins that are involved in the binding or transport of these metals have major effects on Salmonella virulence. Correspondingly, mutations in the mammalian divalent metal transporter Nrampl result in increased susceptibility to Salmonella infection. Based on these observations, I hypothesized that mammalian metal transporters other than Nramp1 might also influence Salmonella-host cell interactions. In support of this idea, I present preliminary evidence showing that the iron efflux protein ferroportin 1 (FPN1), a member of the solute carrier (SLC) family of transporters that includes Nramp1, significantly inhibits the intracellular growth of Salmonella when expressed in HeLa cells. The experiments in this proposal will extend this line of investigation to: (a) Elucidate the mechanism of the bacteriostatic effect of FPN1, by examining its sub-cellular localization, involvement of its iron transport function in bacteriostasis, and its effects on movement of iron into or out of the phagosome. (b) Clarify the role of FPN1 in the growth of Salmonella inside macrophages, the cell type that is chronically infected by this organism in vivo in systemic disease, using siRNA technology to knock-down expression of the protein, (c) Identify other metal ion transporters of the SLC family that might influence the intracellular growth of Salmonella by using an siRNA-based functional screen of all such transporters in the mouse genome. These studies will identify new aspects of the Salmonella-host cell interaction, shed light on the role of mammalian metal transporters in Salmonella infection, and suggest novel approaches to treating salmonellosis.
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