CD8+ T cell effectors against microsporidia

对抗微孢子虫的 CD8 T 细胞效应

• 批准号: 8700315
• 负责人: IMTIAZ AHMED KHAN
• 金额: $ 39.92万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-17 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700315
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adopted; Albendazole; Animals; Biological Assay; Blood; Body Weight decreased; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cells; Child; Clinical; Data; Defect; Development; Diagnosis; Diarrhea; Effector Cell; Elderly; Encephalitozoon cuniculi; Encephalitozoon hellem; Enterocytozoon bieneusi; Exhibits; Generations; Geographic Locations; Goals; HIV; HIV Infections; Hand; Heterogeneity; Human; Immune; Immune response; Immunity; Immunocompromised Host; Immunotherapeutic agent; Impairment; Individual; Infection; Interferons; Kinetics; Knock-out; Laboratories; Lead; Link; Maintenance; Mediating; Memory; Methods; Microsporidia; Microsporidiosis; Modeling; Mono-S; Mus; Opportunistic Infections; Organ Transplantation; Organism; Parasite Control; Parasites; Patients; Persons; Pharmaceutical Preparations; Play; Population; Population Study; Predisposition; Prevalence; Production; Risk; Role; Septata intestinalis; Source; Symptoms; System; Systemic disease; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Transplant Recipients; Vaccines; Viral; adaptive immunity; base; cytokine; fumagillin; improved; interest; novel therapeutic intervention; oral infection; pathogen; perforin; public health relevance; response; socioeconomics

DESCRIPTION (provided by applicant): Microsporidial infection continues to be a problem for HIV infected individuals and are associated as a cause of persistent diarrhea and systemic disease in these people. Recent studies have also implicated these agents in causing illness to HIV- negative groups like travelers and immuno-competent elderly individuals. The limited studies available with Encephalitozoon cuniculi, a microsporidia that can be easily cultured in the laboratory have demonstrated importance of T cells in protection against the parasite. Amongst the T cell subsets, CD8+ T lymphocytes are primary effector cells responsible for protective immunity with CD4+ and ?¿ T playing an important helper role. Knock out animals lacking either of the two subsets exhibit sub-optimal CD8+ T cell immunity to E.cuniculi infection. Recent studies from our laboratory suggest that IL- 21, a cytokine produced by both CD4 and ?¿ T cells, is important for the induction of multifunctional CD8+T cell response against the pathogen. Neutralization of IL-21 response leads to decreased polyfunctional and increased mono-functional CD8+ T cell response as a result of which they are less protective and the host is unable to clear infection in an efficient manner. Importance of poly or multifunctional CD8+ T cells has recently been associated with increased protection against viral pathogens, although the direct link has yet to established. Thus it appears that IL-21 mediated polyfunctional CD8+ T cell response is key to protection against E.cuniculi infection which poses a risk to HIV infected population. The proposal comprises of three specific aims. In the first specific aim the kinetics o IL-21 response by ?¿ and CD4+ T cell population in response to E.cuniculi infection will be evaluated. The mechanism of IL-21 production and priming of CD8+ T cell response against the pathogen will be assayed. In the second specific aim role of IL-21 in the development of polyfunctional CD8+ T cell effector response will be determined. Further, importance of polyfunctionality in the development of robust long-term response will be analyzed. In the third and final specific aim various strategies which can lead to induction and maintenance of polyfunctional CD8+ T cell response in immunocompromised (like HIV-infected) host will be tested and therapeutic role of IL-21 in this situation will be evaluated. These studies will have fr reaching implications in other opportunistic infections and viral pathogens where development of robust CD8+ T cell response is critical for host protection.

描述（由申请人提供）：微孢子虫感染仍然是 HIV 感染者面临的一个问题，并且是这些人持续性腹泻和全身性疾病的原因之一。最近的研究还表明，这些病原体会导致 HIV 阴性人群患病。对兔脑炎寄生虫（一种可以在实验室中轻松培养的微孢子虫）进行的有限研究已经证明了 T 细胞在预防寄生虫方面的重要性。亚群中，CD8+ T 淋巴细胞是负责 CD4+ 和 ?¿ 的保护性免疫的主要效应细胞T 发挥着重要的辅助作用。敲除缺乏这两个亚群中的任何一个的动物对 E. cuniculi 感染表现出次优的免疫。我们实验室的最新研究表明，IL-21（一种由 CD4 和 β 产生的细胞因子）。 T 细胞对于诱导针对病原体的多功能 CD8+T 细胞反应非常重要，IL-21 反应的中和会导致多功能 CD8+T 细胞反应减少和单功能 CD8+T 细胞反应增加，从而导致它们对宿主的保护作用减弱。最近发现，多功能 CD8+ T 细胞的重要性与增强对病毒病原体的保护有关，尽管尚未建立直接联系，因此看来 IL-21 介导了有效的多功能 CD8+。 T 细胞反应是防止兔 E. cuniculi 感染的关键，该感染对 HIV 感染人群构成风险。该提案包括三个具体目标：第一个具体目标是 IL-21 反应的动力学。在IL-21在开发中的第二个具体目标作用中，将评估IL-21产生的机制以及针对病原体的CD8+T细胞反应的启动。此外，在第三个也是最后一个具体目标中，将分析多功能性在产生强大的长期反应中的重要性，这些策略可以导致多功能性的诱导和维持。将测试免疫功能低下（如感染 HIV 的）宿主中的 CD8+ T 细胞反应，并评估 IL-21 在这种情况下的治疗作用。这些研究将对其他机会性感染和病毒病原体产生强大的 CD8+ T 细胞发育影响。响应对于宿主保护至关重要。