Human Cellular Immune Responses to Leptospira

人类细胞对钩端螺旋体的免疫反应

• 批准号: 7009958
• 负责人: GARY R. KLIMPEL
• 金额: $ 57.17万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009958
• 关键词: Peru; SDS polyacrylamide gel electrophoresis; Spirochaetales; T cell receptor; T lymphocyte; apoptosis; bacterial antigens; bacterial cytopathogenic effect; cell cell interaction; cell proliferation; cellular immunity; clinical research; cytotoxicity; disease /disorder etiology; enzyme linked immunosorbent assay; host organism interaction; human subject; hyperthermia; leukocyte activation /transformation; lipopolysaccharides; major histocompatibility complex; microorganism culture; microorganism immunology; patient oriented research; receptor expression; spirochetes disease

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（由申请人提供）：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疾病，通过受感染哺乳动物的尿液传播给人类。 它在世界各地的温带和热带气候中都有发现，对美国和国外的公共卫生构成威胁。 人类感染钩端螺旋体有广泛的临床表现，从无症状血清转化为未分化发热综合征，伴或不伴无菌性脑膜炎，到暴发性黄疸、肾功能衰竭和出血，死亡率高达约 25%。 没有疫苗可以预防人类钩端螺旋体病，并且由于毒性，兽用疫苗可能无法用于人类。 关于这种生物体如何与人类淋巴细胞相互作用和/或钩端螺旋体发病机制或免疫机制知之甚少。 我们建议检查钩端螺旋体与人外周血单核细胞 (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，钩端螺旋体激活未接触过钩端螺旋体的人类 PBMC 中的 T 细胞，导致增殖并产生高水平的 IFN γ。 我们的假设是，表达抗原 T 细胞受体 α/β 或 γ/δ 形式的 T 细胞的钩端螺旋体激活在与钩端螺旋体属引起的人类感染相关的保护性免疫和免疫发病机制中发挥重要的调节作用。 我们的目标是： 1) 确定暴露于钩端螺旋体的 PBMC 培养物的细胞：细胞相互作用和细胞因子谱，并表征在此类培养物中激活的 T 细胞的表型、功能和特异性； 2）鉴定并纯化激活T细胞的钩端螺旋体成分； 3) 确定秘鲁亚马逊流行区人类钩端螺旋体病患者的外周血T细胞表型和功能以及疾病严重程度之间的关系。 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病理。