Immune Correlates and Mechanisms of Controlling NTS Bacteremia

免疫相关性和控制 NTS 菌血症的机制

基本信息

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
项目类别：
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

项目摘要

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.

非细类沙门氏菌（NTS）将食用动物定居，并在美国引起人类胃肠道，每年销售数十亿美元。 NT还会引起免疫功能低下的个体（包括癌症或自身免疫性疾病的患者）的菌血症，或服用免疫抑制药物治疗的人。艾滋病毒感染的个体和艾滋病的适合素也处于危险之中，因此对NTS菌血症的易感性是全世界共有的一个问题。在艾滋病毒流行病的热带非洲，人群还遭受营养不良，水质差以及疟疾和蠕虫的侵扰，所有这些都改变了宿主的免疫反应，因此可疑对NTS感染。尽管控制NTS菌血症所需的宿主反应和非洲NTS的流行病学都没有很好地研究，但最近的数据表明，NTS的人类对人类对人类的传播。因此，扩大的可疑宿主人群患有NTS菌血症，并通过人类到人类的传播，暴露了其他免疫系统的其他宿主，这些宿主因其他感染，年轻年龄或其他侮辱而造成了可观的损害。从而在糟糕的一部分中创建一个新的宿主病原体“生态系统”。这种独特的环境可能允许使用具有改变特性的NTS菌株的繁殖，尤其是与美国的NTS堂兄相比动物对人类。 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源源不断可用于疫苗蛋白质抗血症的疫苗。该项目由项目1和2中所述的工作产生的试剂旨在增强，并提供了机械数据，以帮助解释项目1中收集的临床数据，并提供实验系统，以进一步评估项目2中定义的感兴趣菌株。