Modulation of schistosome development by T cell signals

T 细胞信号调节血吸虫发育

基本信息

批准号：
7179334
负责人：
Stephen J Davies
金额：
$ 36.78万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7179334
关键词：
Accounting Address Affect Africa Animals Antigens Area Asia Bacteria Biological Biological Models CD4 Positive T Lymphocytes Cell Communication Cell Survival Cell physiology Cells Complex Condition Coupled Data Development Disease Disruption Foundations Genome Goals Helminths Human Human Resources IL2RA gene Immunity Immunocompetent Immunodeficient Mouse Immunotherapy Infection Infection prevention Integration Host Factors Interleukin-2 Intestines Laboratory Study Life Life Cycle Stages Liver Mediating Modeling Molecular Morbidity - disease rate Mus Outcome Parasites Parasitic Diseases Pathology Peace Corps Peptides Plastics Play Population Process Program Development Public Health Rate Reproduction Research Personnel Resistance development Role Schistosoma Schistosoma mansonii infection Schistosomatidae Schistosomiasis Services Signal Transduction South America Specificity Staging System T-Cell Development T-Lymphocyte Testing Therapeutic Tissues Transgenic Organisms Urinary system Vaccines Virus Visit base cytokine in vivo in vivo Model migration mortality mouse model novel strategies pathogen prevent programs prophylactic reconstitution response transmission process

项目摘要

DESCRIPTION (provided by applicant): Schistosomiasis, the parasitic disease caused by blood flukes of the genus Schistosoma, causes potentially serious liver, intestine and urinary system pathology in approximately 200 million people worldwide, resulting in significant morbidity and mortality. In addition to constituting a major public health concern for people living in endemic areas in South America, Africa and Asia, schistosomiasis is also a significant concern for U.S. service personnel, Peace Corps workers and civilians visiting regions where blood flukes are prevalent. High re-infection rates following treatment and the potential for development of resistance to the few effective chemotherapeutics for schistosomiasis has prompted efforts to develop vaccines that prevent infection and/or disease. While an effective vaccine has not yet been developed, evidence from field and laboratory studies indicate that CD4+ T cell responses will be critical components of the response induced by an effective vaccine. However, our studies using a murine model of schistosome infection have demonstrated that, paradoxically, schistosomes also require signals from host CD4+ T cells to complete their development normally, suggesting that blocking interactions between parasite and host T cells might provide a novel approach to interfering with parasite development. The long-term objective of our studies is to contribute to the development of new immunotherapies aimed at preventing schistosome development in the definitive human host, thus simultaneously preventing the pathology associated with schistosome infection and blocking parasite transmission. The overall aim of this study is to further our understanding of the role CD4+ T cells play in facilitating the development and reproduction of Schistosoma blood flukes. The specific aims of this study are (1) to determine whether the presence of CD4* T cells alone is sufficient to facilitate parasite development, (2) to determine whether CD4+ T cell responses to schistosome antigens are important in influencing the outcome of schistosome development, and (3) determine the role of the CD4+ T cell cytokine interleukin-2 (IL-2) in affecting the outcome of schistosome development. Specific aim 1 will be accomplished by examining schistosome infections in a transgenic mouse model where none of the animal's CD4+ T cells are able to respond to schistosome antigens because of their restricted specificity for an unrelated antigen. Specific aim 2 will be accomplished by selectively reconstituting immunodeficient mice with CD4+ T cells that can or cannot respond to schistosome antigens prior to infection and then examining the effect of activation with the appropriate antigen on parasite development. Specific aim 3 will be addressed by examining schistosome infection in IL-2-deficient mice.

描述（由申请人提供）：血吸虫病是由血吸虫属血吸虫引起的寄生虫病，可能导致全世界约 2 亿人出现严重的肝脏、肠道和泌尿系统病变，导致显着的发病率和死亡率。血吸虫病除了构成南美洲、非洲和亚洲流行地区居民的主要公共卫生问题外，也是访问血吸虫流行地区的美国军人、和平队工作人员和平民的一个重大问题。治疗后的高再感染率以及对少数有效的血吸虫病化疗药物产生耐药性的可能性，促使人们努力开发预防感染和/或疾病的疫苗。虽然尚未开发出有效的疫苗，但现场和实验室研究的证据表明 CD4+ T 细胞反应将是有效疫苗诱导反应的关键组成部分。然而，我们使用血吸虫感染的小鼠模型进行的研究表明，矛盾的是，血吸虫也需要宿主 CD4+ T 细胞的信号才能正常完成其发育，这表明阻断寄生虫和宿主 T 细胞之间的相互作用可能提供一种干扰寄生虫的新方法。寄生虫的发育。我们研究的长期目标是促进新的免疫疗法的开发，旨在预防最终人类宿主中血吸虫的发展，从而同时预防与血吸虫感染相关的病理并阻止寄生虫传播。本研究的总体目的是进一步了解 CD4+ T 细胞在促进血吸虫发育和繁殖中的作用。本研究的具体目的是 (1) 确定仅 CD4* T 细胞的存在是否足以促进寄生虫发育，(2) 确定 CD4+ T 细胞对血吸虫抗原的反应是否对影响血吸虫发育的结果很重要，(3) 确定 CD4+ T 细胞细胞因子白细胞介素 2 (IL-2) 在影响血吸虫发展结果中的作用。具体目标 1 将通过检查转基因小鼠模型中的血吸虫感染来实现，其中动物的 CD4+ T 细胞均无法对血吸虫抗原做出反应，因为它们对不相关抗原的特异性有限。具体目标 2 将通过选择性地用 CD4+ T 细胞重建免疫缺陷小鼠来实现，这些细胞在感染前可以或不能对血吸虫抗原作出反应，然后检查适当抗原的激活对寄生虫发育的影响。具体目标 3 将通过检查 IL-2 缺陷小鼠的血吸虫感染来解决。