Immune Correlates and Mechanisms of Controlling NTS Bacteremia

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Non-typhoidal Salmonella (NTS) colonizes food animals and causes human gastroenterifis in the U.S., cosfing billions of dollars annually. NTS also causes bacteremia in immunocompromised individuals, including those with cancer or autoimmune diseases, at the extremes of age, or those taking immunosuppressive medicafions. HIV infected individuals and AIDS pafients are also at risk, and thus susceptibility to NTS bacteremia is a problem shared throughout the world. In tropical Africa, where HIV is epidemic, the populafion also suffers from malnutrition, poor water quality, and infestations with malaria and helminthes, all of which alter host immune responses and therefore suscepfibility to NTS infections. Although neither the host responses required for controlling NTS bacteremia nor the epidemiology of NTS infecfions in Africa are well studied, recent data indicates human-to-human transmission of NTS. Thus, an enlarging population of suscepfible hosts suffers NTS bacteremia and, through human-to-human transmission, exposes other hosts with immune systems variably compromised by additional infections, young age, or other insults; thereby creating a new host-pathogen 'ecosystem' in one part of the worid. This unique environment may be permissive for propagation of NTS strains with altered properties, especially in comparison with their NTS cousins from the U.S. where transmission most commonly occurs from food animal to humans. This project will test interrelated hypotheses directed toward understanding immune mechanisms controlling NTS bacteremia and the attributes of bacterial strains arising in this unique environment: 1) altered immune detecfion, relevant to colonizing and causing bacteremia in immunocompromised hosts, has arisen in NTS strains as a result of human-to-human transmission, 2) interrelated immune functions, including T and B cell, macrophage and cytokine funcfions are important for controlling bacteremia, 3) specific immune defects, relevant to our study populations, facilitate NTS colonizafion/bacteremia, and 4) examining differenfial immune recognition of NTS isolates by bacteremic patients and their close contacts will aid us in establishing screening criteria for Salmonella carrier status and provide preliminary indicators of bacterial anfigens potentially useful for vaccines protecfive against bacteremia. This project is substanfially enhanced by reagents resulting from the work described in Projects 1 and 2, provides mechanistic data to aid in the interpretation of clinical data gathered in Project 1, and provides experimental systems for further evaluating strains of interest defined in Project 2.