CD8+ T cell effectors against microsporidia

对抗微孢子虫的 CD8 T 细胞效应

• 批准号: 8329808
• 负责人: IMTIAZ AHMED KHAN
• 金额: $ 41.39万
• 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/8329808
• 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; 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. PUBLIC HEALTH RELEVANCE: Microsporidial infection poses a problem for immunocompromised patients like those carrying HIV infection. The goal of this proposal is to understand the immune response needed for the controlling this pathogen so that immunotherapeutic agents needed to protect immuno-deficient subjects and be developed

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。最近的研究还表明，这些药物也会引起艾滋病毒阴性群体的疾病，如旅行者和有免疫能力的老年人。可用的有限的研究与脑炎原虫，可以很容易地在实验室中培养的微孢子虫已经证明了T细胞在保护免受寄生虫的重要性。在T细胞亚群中，CD 8 + T淋巴细胞是主要的效应细胞，负责与CD 4+和？T扮演一个重要的助手角色。缺乏两个亚群中的任一个的敲除动物表现出对兔艾美耳球虫感染的次优CD 8 + T细胞免疫。我们实验室最近的研究表明，IL- 21，一种由CD 4和CD 4+细胞产生的细胞因子，T细胞，对于诱导针对病原体的多功能CD 8 +T细胞应答是重要的。IL-21应答的中和导致多功能性CD 8 + T细胞应答降低和单功能性CD 8 + T细胞应答增加，因此它们的保护性较低，并且宿主不能以有效的方式清除感染。多功能或多功能CD 8 + T细胞的重要性最近与增加对病毒病原体的保护有关，尽管直接联系尚未建立。因此，IL-21介导的多功能CD 8 + T细胞应答似乎是保护免受对HIV感染人群构成风险的兔艾美耳球虫感染的关键。该提案包括三个具体目标。在第一个具体目标中，通过？将评估响应于兔艾美耳球虫感染的CD 4 + T细胞群。将分析IL-21产生的机制和针对病原体的CD 8 + T细胞应答的引发。在第二个具体目标中，将确定IL-21在多功能CD 8 + T细胞效应子应答的发展中的作用。此外，将分析多功能性在发展稳健的长期反应中的重要性。在第三个和最后一个具体目标中，将测试可以导致在免疫受损（如HIV感染）宿主中诱导和维持多功能CD 8 + T细胞应答的各种策略，并将评估IL-21在这种情况下的治疗作用。这些研究将在其他机会性感染和病毒病原体中产生深远的影响，其中稳健的CD 8 + T细胞应答的发展对于宿主保护至关重要。 公共卫生相关性：微孢子虫感染对免疫功能低下的患者（如HIV感染者）构成了一个问题。本提案的目的是了解控制这种病原体所需的免疫应答，以便开发保护免疫缺陷受试者所需的免疫抑制剂。