Immune Correlates and Mechanisms of Controlling NTS Bacteremia

在美国，非伤寒沙门氏菌（NTS）寄生于食用动物并引起人类肠胃炎，每年造成数十亿美元的损失。NTS还会在免疫功能低下的个体中引起菌血症，包括那些患有癌症或自身免疫性疾病的人，在极端年龄，或服用免疫抑制药物的人。艾滋病毒感染者和艾滋病患者也面临风险，因此易患NTS菌血症是全世界共同面临的问题。在艾滋病毒流行的热带非洲，人们还遭受营养不良、水质差以及疟疾和寄生虫的侵扰，所有这些都改变了宿主的免疫反应，因此易受NTS感染。虽然控制NTS菌血症所需的宿主反应和非洲NTS感染的流行病学都没有得到很好的研究，但最近的数据表明NTS在人与人之间传播。因此，越来越多的易感宿主遭受NTS菌血症，并通过人与人之间的传播，使免疫系统因其他感染、年轻或其他侮辱而受到不同程度损害的其他宿主暴露在外；从而在世界的一个地区创造了一个新的宿主-病原体“生态系统”。这种独特的环境可能允许具有改变特性的NTS菌株的繁殖，特别是与来自美国的NTS表亲相比，后者最常通过食物传播

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.