Regulation of Innate Immunity to Enterocytozoon bieneusi Infection

对比氏肠细胞虫感染的先天免疫的调节

• 批准号: 7151088
• 负责人: SAUL r TZIPORI
• 金额: $ 22.11万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151088
• 关键词: genes; immunity; infection; role

DESCRIPTION (provided by applicant): This R21 application is in response to RFA-AI-05-042 on Innate Immunity to Category B pathogens of which Enterocytozoon bieneusi, a Microsporidium previously classified as protozoa. Of the 14 species affecting human health E. bieneusi is clinically the most significant emerging enteric pathogen that infects the gastrointestinal tract of most mammalian species, and is the major cause of chronic diarrhea, wasting and cholangitis in patients with HIV/AIDS, malnourished children and those receiving immunosuppressive therapy. The technical difficulties that were associated with the lack of in vitro laboratory propagation methods as well as limited sources of spores, has contributed to the very slow progress on understanding the biology, pathogenesis and protective immune responses against this emerging pathogen. These have to a large extent been overcome recently by our group, which provides the impetus to this application. The long term goal of this application is to enhance our understanding of the mechanisms involved in E. bieneusi protective immunity. This information is critical for the development of effective immunotherapeutic approaches that may help resolve otherwise a fatal infection in immunodeficient individuals. Our preliminary data indicate that IFN-gamma is an important component in providing initial resistance to E. bieneusi infection. An investigation into the molecular basis of cellular activation by E bieneusi, including a characterization of the innate immune receptors that initiate this initial resistance is unknown. The goals of this application are to identify the specific cellular receptors and adaptor proteins that are responsible for initiating innate immunity during E. bieneusi infection, and to determine which IFN-gamma-dependent components are regulated by the host immune system during infection of epithelial cells. The role of TLRs in innate immunity and the IFN-gamma regulated genes that are essential in the context of this infection, will be investigated. The specific aims are: 1. To examine the expression of E. bieneusi-specific IFN-gamma regulated genes that may be involved in innate immunity to infection. 2. To determine the role of Toll-like receptors (TLR)/MyD88 signaling pathway, in the induction of IFN-gamma, in response to E. bieneusi infection. Elucidation of the mechanistic basis of regulation of the innate immunity will lead to a better understanding of resistance to E. bieneusi infection. Moreover, innate immunity significantly affects the generation of acquired immunity to many infections. Thus, the proposed studies will form a foundation on which to build further studies to examine how regulation of innate immunity impacts acquired immunity to this emerging infection.

描述（由申请人提供）：本 R21 申请是对关于 B 类病原体先天免疫的 RFA-AI-05-042 的回应，其中肠细胞虫 bieneusi 是一种以前被分类为原生动物的微孢子虫。在影响人类健康的 14 个物种中，E. bieneusi 是临床上最重要的新出现的肠道病原体，它感染大多数哺乳动物物种的胃肠道，并且是艾滋病毒/艾滋病患者、营养不良儿童和儿童慢性腹泻、消瘦和胆管炎的主要原因。接受免疫抑制治疗的人。与缺乏体外实验室繁殖方法以及孢子来源有限相关的技术困难导致对这种新兴病原体的生物学、发病机制和保护性免疫反应的了解进展非常缓慢。我们的团队最近在很大程度上克服了这些问题，这为该应用提供了动力。该应用的长期目标是增强我们对 E. bieneusi 保护性免疫机制的理解。这些信息对于开发有效的免疫治疗方法至关重要，这些方法可能有助于解决免疫缺陷个体的致命感染。我们的初步数据表明，IFN-gamma 是提供对 E. bieneusi 感染的初始抵抗力的重要组成部分。对 E bieneusi 细胞激活的分子基础的研究，包括启动这种初始抵抗的先天免疫受体的特征，尚不清楚。该应用的目标是鉴定在 E. bieneusi 感染期间负责启动先天免疫的特定细胞受体和衔接蛋白，并确定哪些 IFN-γ 依赖性成分在上皮细胞感染期间受到宿主免疫系统的调节。将研究 TLR 在先天免疫中的作用以及在这种感染中至关重要的 IFN-γ 调节基因。具体目标是： 1. 检查 E. bieneusi 特异性 IFN-gamma 调节基因的表达，这些基因可能参与对感染的先天免疫。 2. 确定Toll样受体（TLR）/MyD88信号通路在IFN-γ诱导中的作用， 响应 E. bieneusi 感染。阐明先天免疫调节的机制基础将有助于更好地了解对 E. bieneusi 感染的抵抗力。此外，先天免疫显着影响许多感染的获得性免疫的产生。因此，拟议的研究将为进一步研究奠定基础，以检验先天免疫的调节如何影响对这种新出现的感染的获得性免疫。