Organisms belonging to the infection in patients with AIDS. In contrast with non-AIDS individuals, in AIDS patients M. avium is primarily acquired through the gastrointestinal tract. Following colonization of the intestines, M. avium invades the intestinal mucosa and secondarily infects submucosal macrophages and monocytes. Once within macrophages, M. avium inhibits acidification and maturation of phagosomes, creating conditions for replication and survival, and subsequently dissemination. The genes which are associated with invasion and intracellular survival are keys for M. avium pathogenesis. However, thus far only a few putative virulence genes have been identified on M avium. The applicants propose to develop genetic systems that will allow the identification of genes that are associated with virulence. More specifically, they will develop genetic systems in M. avium for: 1. Isolation and novel virulence determinants associated with binding, invasion and persistence within intestinal epithelial cells and macrophages using transposon mutagenesis and reporter gene systems 2 knockout mutagenesis of previously identified putative virulence genes. The investigators plan to focus their effort on two previously described genes, sodA and fapA. 3. Complementation of the resulting mutation to restore virulence. The applicants believe that the studies outlined in this proposal will provide excellent tools for the identification of novel genes associated with mechanisms of pathogenesis of M. avium.m.
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