Human Cellular Immune Responses to Leptospira

人类细胞对钩端螺旋体的免疫反应

• 批准号: 7174227
• 负责人: GARY R. KLIMPEL
• 金额: $ 56.96万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174227
• 关键词: Anti-Bacterial Agents; Apoptosis; Aseptic Meningitis; CD4 Positive T Lymphocytes; Case Fatality Rates; Cell Communication; Cells; Clinical; Detergents; Disease; Fever; Fractionation; Frequencies; Goals; Hemorrhage; Human; Icterus; Immune response; Immune system; Immunity; In Vitro; Infection; Interferon Type II; Kidney Failure; Kinetics; Lead; Learning; Leptospira; Leptospirosis; Lipopolysaccharides; Lymphocyte; Mammals; Mediating; Molecular; Natural History; Order Spirochaetales; Organism; Pathogenesis; Pathology; Patients; Peptidoglycan; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Plasma; Play; Population; Production; Proliferating; Public Health; Range; Rate; Role; Severity of illness; Specificity; Syndrome; T-Cell Activation; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Time; Toxic effect; Tropical Climate; Undifferentiated; United States; Urine; Vaccines; base; cytokine; cytotoxic; killings; molecular mass; peripheral blood; prevent; response

DESCRIPTION (provided by applicant): Leptospirosis, a zoonotic disease caused by spirochetes of the genus Leptospira, is transmitted to humans via urine of infected mammals. Found worldwide in temperate and tropical climates, it is a public health threat in the U.S. and abroad. Human infections by Leptospira have a broad spectrum of clinical manifestations, ranging from asymptomatic seroconversion to undifferentiated febrile syndrome, with or without aseptic meningitis, to fulminant jaundice, renal failure and hemorrhage with a fatality rate up to approximately 25%. There is no vaccine to prevent human leptospirosis and veterinary vaccines may not be used in humans because of toxicity. Little is known about how this organism interacts with human lymphocytes and/or the mechanisms of leptospiral pathogenesis or immunity. We propose to examine molecular and cellular interactions of Leptospira with human peripheral blood mononuclear cells (PBMC) with a focus on different T cell populations. We have found that leptospires activate T cells in PBMC from Leptospira-naive humans, leading to proliferation and production of high IFN gamma levels. Our hypothesis is that Leptospira activation of T cells expressing the alpha/beta or gamma/delta form of the T cell receptor for antigen plays an important regulatory role in protective immunity and immunopathogenesis associated with human infections due to Leptospira spp. Our aims are to: 1) Determine the cell:cell interactions and cytokine profiles of PBMC cultures exposed to Leptospira, and characterize the phenotype, function, and specificity of T cells activated in such cultures; 2) Identify and purify Leptospira components that activate T cells; and 3) Determine the relationship between peripheral blood T cell phenotype and function and disease severity of human leptospirosis patients in an endemic region in the Peruvian Amazon. Learning how Leptospira interact with the human immune system will lead us to understand the pathogenesis of leptospirosis and how to develop vaccines and strategies to control the associated pathology.

描述(申请人提供)：钩端螺旋体病是一种由钩端螺旋体属螺旋体引起的人畜共患病，通过受感染的哺乳动物的尿液传播给人类。它分布在世界各地的温带和热带气候中，在美国和国外都是一种公共健康威胁。人类感染钩端螺旋体具有广泛的临床表现，从无症状的血清转换到未分化的发热综合征，无论是否有无菌性脑膜炎，再到暴发性黄疸、肾功能衰竭和出血，病死率高达约25%。目前还没有预防人类钩端螺旋体病的疫苗，由于毒性，兽医疫苗可能不会在人类身上使用。关于这种微生物如何与人淋巴细胞相互作用和/或钩端螺旋体的致病或免疫机制，人们知之甚少。我们建议研究钩端螺旋体与人外周血单个核细胞(PBMC)的分子和细胞相互作用，重点关注不同的T细胞群。我们发现钩端螺旋体能激活未感染钩端螺旋体的人PBMC中的T细胞，导致细胞增殖并产生高水平的干扰素-γ。我们的假设是，钩端螺旋体激活表达抗原T细胞受体的α/β或γ/delta型的T细胞，在保护性免疫和与钩端螺旋体感染相关的免疫发病机制中起着重要的调节作用。我们的目标是：1)确定暴露于钩端螺旋体的PBMC培养的细胞：细胞相互作用和细胞因子谱，并表征在此类培养中激活的T细胞的表型、功能和特异性；2)鉴定和纯化激活T细胞的钩端螺旋体成分；以及3)确定秘鲁亚马逊流行区人类钩端螺旋体病患者外周血T细胞表型与功能和疾病严重程度的关系。了解钩端螺旋体如何与人类免疫系统相互作用将引导我们了解钩端螺旋体病的发病机制，以及如何开发疫苗和策略来控制相关的病理。