Immune Correlates and Mechanisms of Controlling NTS Bacteremia

免疫相关性和控制 NTS 菌血症的机制

• 批准号: 8026709
• 负责人: BRAD T COOKSON
• 金额: $ 38.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8026709
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Adenoviruses; Adult; Africa; Age; American; Animal Feed; Animal Model; Animals; Antibodies; Antibody Formation; Antigenic Specificity; Antigens; Architecture; Attenuated; Autoimmune Diseases; B-Lymphocytes; Bacteremia; Bacteria; Biological Assay; CD4 Positive T Lymphocytes; Carbohydrates; Caspase-1; Cattle; Cell Death; Cells; Child; Chronic; Clinical Data; Data; Defect; Dendritic Cells; Detection; Development; Ecosystem; Environment; Epidemic; Epidemiology; Feces; Figs - dietary; Flagellin; Gene Transfer; Goals; Growth; HIV; Helminths; Histologic; Histology; Host Defense; Hour; Human; IL10 gene; Immune; Immune Sera; Immune response; Immune system; Immunocompromised Host; Immunoglobulin G; Immunoglobulins; Immunosuppressive Agents; Individual; Infant; Infection; Inflammation; Inflammatory; Interleukin-10; Interleukin-12; Invaded; Liposomes; Liquid substance; Lymphocyte; Malaria; Malignant Neoplasms; Malnutrition; Measures; Mediating; Mediator of activation protein; Mesentery; Modeling; Modification; Monitor; Mus; Oral; Pathogenesis; Patients; Population; Population Study; Predisposition; Property; Proteins; Reagent; Risk; Role; Salmonella; Salmonella infections; Screening procedure; Serum; Spleen; Splenomegaly; Surface; System; Systemic infection; T-Lymphocyte; Testing; Tissue Sample; Tissues; United States; Vaccines; Virulence; Virulent; Western Blotting; Work; cytokine; cytotoxicity; fluorescence imaging; genetic regulatory protein; immune function; in vivo; indexing; interest; intestinal epithelium; lymph nodes; macrophage; mouse model; neutrophil; overexpression; pathogen; response; tool; transmission process; water quality

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.

非伤寒沙门氏菌(NTS)在美国定植食用动物并导致人类胃肠炎，每年造成数十亿美元的损失。NTS还会在免疫受损的人中引起菌血症，包括那些患有癌症或自身免疫性疾病的人，处于极端年龄的人，或者那些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，因此对NTS菌血症的易感性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、水质差以及疟疾和蠕虫的感染，所有这些都会改变宿主的免疫反应，因此容易受到非传染性疾病的感染。尽管控制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患有NTS菌血症，并通过人与人之间的传播，使其他宿主暴露于免疫系统因其他感染、年轻或其他侮辱而受到不同程度的损害；从而在世界的某一部分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近亲相比，在美国，NTS最常见的传播途径是食物 从动物到人类。这个项目将测试相互关联的假说，旨在了解控制NTS菌血症的免疫机制和在这个独特环境中出现的细菌菌株的属性：1)由于人与人的传播，在免疫受损的宿主中出现了与定植和引起菌血症相关的免疫检测改变，2)相互关联的免疫功能，包括T和B细胞、巨噬细胞和细胞因子功能对控制菌血症非常重要，3)与我们的研究人群相关的特定免疫缺陷，促进NTS定植/菌血症，4)检测菌血症患者及其密切接触者对NTS分离株的不同免疫识别能力将有助于我们建立沙门氏菌携带者状态的筛选标准，并为可能用于预防菌血症的疫苗提供初步的细菌形态指标。该项目通过项目1和2中描述的工作所产生的试剂进行了实质性的增强，提供了机械数据来帮助解释项目1中收集的临床数据，并为进一步评估项目2中定义的感兴趣的菌株提供了实验系统。