Immune Correlates and Mechanisms of Controlling NTS Bacteremia

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Non-typhoidal Salmonella (NTS) colonizes food animals and causes human gastroenteritis in the U.S., costing 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 medications. HIV infected individuals and AIDS patients 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 population also suffers from malnutrition, poor water quality, and infestations with malaria and helminthes, all of which alter host immune responses and therefore susceptibility to NTS infections. Although neither the host responses required for controlling NTS bacteremia nor the epidemiology of NTS infections in Africa are well studied, recent data indicates human-to-human transmission of NTS. Thus, an enlarging population of susceptible 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 world. 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 detection, 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 functions are important for controlling bacteremia, 3) specific immune defects, relevant to our study populations, facilitate NTS colonization/bacteremia, and 4) examining differential 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 antigens potentially useful for vaccines protective against bacteremia. This project is substantially 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.