CD8+ T cell effectors against microsporidia

对抗微孢子虫的 CD8 T 细胞效应

• 批准号: 8532815
• 负责人: IMTIAZ AHMED KHAN
• 金额: $ 37.53万
• 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/8532815
• 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; 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感染者的一个问题，并与这些人持续腹泻和全身性疾病的原因有关。最近的研究也表明，这些病原体会导致旅行者和免疫能力强的老年人等艾滋病毒阴性群体患病。对一种可以在实验室中很容易培养的小孢子虫（Encephalitozoon cucululi）的有限研究已经证明了T细胞在抵抗寄生虫方面的重要性。在T细胞亚群中，CD8+ T淋巴细胞是主要的效应细胞，负责CD4+和？我扮演着重要的助手角色。敲除缺乏两种亚群中的任何一种的动物对虫体感染表现出次优的CD8+ T细胞免疫。我们实验室最近的研究表明，IL- 21，一种由CD4和？T细胞，对于诱导多功能CD8+T细胞对病原体的反应是重要的。IL-21反应的中和导致多功能CD8+ T细胞反应的减少和单功能CD8+ T细胞反应的增加，从而使它们的保护性降低，宿主无法有效地清除感染。多功能性或多功能CD8+ T细胞的重要性最近与增强对病毒病原体的保护有关，尽管直接联系尚未确定。因此，IL-21介导的多功能CD8+ T细胞应答似乎是保护HIV感染者免受毛囊绦虫感染的关键。该建议包括三个具体目标。在第一个具体目标IL-21反应动力学？并评估CD4+ T细胞群对棘球绦虫感染的反应。研究IL-21的产生和CD8+ T细胞对病原体反应的机制。在第二个特定目标中，将确定IL-21在多功能CD8+ T细胞效应反应发展中的作用。此外，将分析多功能性在发展稳健的长期反应中的重要性。在第三个也是最后一个特定目标中，将测试在免疫功能低下（如hiv感染）的宿主中诱导和维持多功能CD8+ T细胞反应的各种策略，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性病原体产生影响，其中CD8+ T细胞反应的发展对宿主保护至关重要。