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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：
7568177
负责人：
Stephen J Davies
金额：
$ 36.08万
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 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7568177
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 Coupled Data Development Disease 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 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 Mice Urinary system Vaccines Virus Visit base cytokine developmental plasticity in vivo in vivo Model migration mortality mouse model novel strategies pathogen prevent programs prophylactic reconstitution response transmission process

项目摘要

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.

血吸虫病是由血吸虫属血吸虫引起的寄生虫病，全世界约2亿人患有严重的肝脏、肠道和泌尿系统病变，发病率和死亡率都很高。除了对生活在美国的人们构成重大的公共卫生问题之外，在南美洲、非洲和亚洲的流行地区，血吸虫病也是美国的一个重要问题。服务人员、和平队工作人员和访问血吸虫流行地区的平民。高治疗后的再感染率和对少数有效药物产生耐药性的潜力血吸虫病的化学疗法促使人们努力开发预防感染的疫苗和/或疾病。虽然尚未开发出有效的疫苗，但来自实地和实验室的证据表明，研究表明，CD 4 + T细胞应答将是由免疫抑制剂诱导的应答的关键组成部分。有效疫苗。然而，我们的研究使用鼠模型的病毒感染已经证明，自相矛盾的是，染色体也需要来自宿主CD 4 + T细胞的信号来完成它们的发育，通常，这表明阻断寄生虫和宿主T细胞之间的相互作用可能会提供一种新的干扰寄生虫发育的方法。我们研究的长期目标是促进新的免疫疗法的发展，在最终的人类宿主中阻止染色体的发育，从而同时阻止与寄生虫感染和阻断寄生虫传播相关的病理学。的总体目标本研究旨在进一步了解CD 4 + T细胞在促进肿瘤发生和发展中的作用，血吸虫的繁殖。本研究的具体目的是：（1）确定单独存在CD 4 + T细胞足以促进寄生虫发育，（2）确定CD 4 + T细胞是否 T细胞对溶酶体抗原的反应在影响溶酶体的结果中是重要的。（3）确定CD 4 + T细胞细胞因子白细胞介素-2（IL-2）在影响发育中的作用。发展缓慢的结果。具体目标1将通过检查在转基因小鼠模型中，没有动物的CD 4 + T细胞能够响应于由于它们对不相关抗原的特异性有限，因此它们是相似的抗原。具体目标2将是通过选择性地用CD 4 + T细胞重建免疫缺陷小鼠来完成，在感染前对病毒体抗原产生反应，然后用适当的抗原对寄生虫的发展。具体目标3将通过审查令人不安的 IL-2缺陷小鼠中的感染。