Modulation of schistosome development by T cell signals

T 细胞信号对血吸虫发育的调节

• 批准号: 7367900
• 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
• 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/7367900
• 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

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引起的寄生疾病，可能引起潜在的 全球大约2亿人的严重肝脏，肠和尿液系统病理学，导致 在明显的发病率和死亡率中。除了构成对生活的人们的主要公共卫生关注 在南美，非洲和亚洲的地方性地区，血吸虫病也是美国的重要关注点 服务人员，和平军团的工作者和平民访问流血很普遍的地区。高的 治疗后的重新感染率以及对少数有效的抵抗力发展的潜力 血吸虫病的化学治疗药促使努力开发防止感染的疫苗 和/或疾病。尽管尚未开发有效的疫苗，但现场和实验室的证据 研究表明，CD4+ T细胞反应将是由A 有效的疫苗。但是，我们使用斑sosos体感染的鼠模型的研究表明 矛盾的是，血吸虫还需要宿主CD4+ T细胞的信号才能完成其发育 通常，表明阻止寄生虫与宿主T细胞之间的相互作用可能会提供新颖 干扰寄生虫发展的方法。 我们研究的长期目标是为旨在的新免疫疗法的发展做出贡献 在防止确定的人类宿主中的血迹发展，从而同时防止 与棘体感染和阻断寄生虫传播相关的病理学。总体目的 这项研究是为了进一步了解CD4+ T细胞在促进发展和 血吸虫血液漏气的繁殖。这项研究的具体目的是（1）确定是否是否 仅存在CD4* T细胞就足以促进寄生虫的发展，（2）确定CD4+是否是否 T细胞对黑螺链体抗原的反应对于影响血块的结果很重要 开发和（3）确定CD4+ T细胞细胞因子白细胞介素2（IL-2）在影响该症状的作用 实体发展的结果。特定的目标1将通过检查实体组来实现 转基因小鼠模型的感染，该模型没有动物的CD4+ T细胞能够反应 血吸虫抗原由于对无关抗原的特异性有限。具体目标2将是 通过有选择地重新建立可以或不能不能或不能无法的CD4+ T细胞来实现的 在感染前对血吸虫抗原做出反应，然后检查激活的作用 寄生虫发育的适当抗原。特定目标3将通过检查实体组来解决 IL-2缺陷小鼠感染。