Immune Correlates and Mechanisms of Controlling NTS Bacteremia

在美国，非伤寒沙门氏菌（NTS）定植于食用动物并引起人类胃肠炎，每年花费数十亿美元。NTS也会导致免疫功能低下的个体菌血症，包括患有癌症或自身免疫性疾病的个体，年龄极端的个体，或服用免疫抑制药物的个体。HIV感染者和AIDS患者也处于危险中，因此对NTS菌血症的易感性是全世界共有的问题。在艾滋病毒流行的热带非洲，人们还遭受营养不良、水质差以及疟疾和蠕虫感染的困扰，所有这些都会改变宿主的免疫反应，从而改变对NTS感染的易感性。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存在人际传播。因此，越来越多的易感宿主患上NTS菌血症，并通过人与人之间的传播，使其他宿主的免疫系统因额外的感染、年幼或其他侮辱而受到损害;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的特性的NTS菌株繁殖，特别是与来自美国的NTS表亲相比，在美国，传播最常见于食物 动物到人类该项目将测试相关的假设，旨在了解控制NTS菌血症的免疫机制以及在这种独特环境中产生的细菌菌株的属性：1）NTS菌株由于人传人而出现了与免疫功能低下的宿主中的定殖和引起菌血症相关的改变的免疫检测，2）相关的免疫功能，包括T和B细胞，巨噬细胞和细胞因子功能对于控制菌血症是重要的，3）与我们的研究群体相关的特异性免疫缺陷，促进NTS定殖/菌血症，和4）的方法检测菌血症患者及其密切接触者对NTS分离株的差异免疫识别将有助于我们建立沙门氏菌携带者状态的筛查标准，并提供初步的细菌抗原的指示物，其可用于预防菌血症的疫苗。该项目通过项目1和2中所述工作产生的试剂得到了显著增强，提供了有助于解释项目1中收集的临床数据的机制数据，并提供了用于进一步评价项目2中定义的目标菌株的实验系统。

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.