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.

Public Health Relevance

Attenuated human immune responses and altered attributes of non-typhoidal Salmonella (NTS) strains resulting from human-to-human transmission could account for epidemic NTS bacteremia in Africa. We investigate the host immune functions required to control NTS bacteremia with the goal of developing screening tools for carrier status and vaccines protective against bacteremia and suitable for immunocompromised hosts.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BLG-M)
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University of Washington
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Singletary, Larissa A; Karlinsey, Joyce E; Libby, Stephen J et al. (2016) Loss of Multicellular Behavior in Epidemic African Nontyphoidal Salmonella enterica Serovar Typhimurium ST313 Strain D23580. MBio 7:e02265
Hayden, Hillary S; Matamouros, Susana; Hager, Kyle R et al. (2016) Genomic Analysis of Salmonella enterica Serovar Typhimurium Characterizes Strain Diversity for Recent U.S. Salmonellosis Cases and Identifies Mutations Linked to Loss of Fitness under Nitrosative and Oxidative Stress. MBio 7:e00154
Akullian, Adam; Ng'eno, Eric; Matheson, Alastair I et al. (2015) Environmental Transmission of Typhoid Fever in an Urban Slum. PLoS Negl Trop Dis 9:e0004212
Pavlinac, Patricia B; Tickell, Kirkby D; Walson, Judd L (2015) Management of diarrhea in HIV-affected infants and children. Expert Rev Anti Infect Ther 13:5-8
LaRock, Doris L; Chaudhary, Anu; Miller, Samuel I (2015) Salmonellae interactions with host processes. Nat Rev Microbiol 13:191-205
Loomis, Wendy P; Johnson, Matthew L; Brasfield, Alicia et al. (2014) Temporal and anatomical host resistance to chronic Salmonella infection is quantitatively dictated by Nramp1 and influenced by host genetic background. PLoS One 9:e111763
Roxby, Alison C; Unger, Jennifer A; Slyker, Jennifer A et al. (2014) A lifecycle approach to HIV prevention in African women and children. Curr HIV/AIDS Rep 11:119-27
Miller, Claire B; Pierlé, Sebastian Aguilar; Brayton, Kelly A et al. (2014) Transcriptional Profiling of a Cross-Protective Salmonella enterica serovar Typhimurium UK-1 dam Mutant Identifies a Set of Genes More Transcriptionally Active Compared to Wild-Type, and Stably Transcribed across Biologically Relevant Microenvironments. Pathogens 3:417-436
Stewart, Mary K; Cookson, Brad T (2014) Mutually repressing repressor functions and multi-layered cellular heterogeneity regulate the bistable Salmonella fliC census. Mol Microbiol 94:1272-84
Stewart, Mary K; Cookson, Brad T (2012) Non-genetic diversity shapes infectious capacity and host resistance. Trends Microbiol 20:461-6

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