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）：此R21申请响应RFA-AI-05-042对B类病原体的先天免疫力，其中肠肠球菌Bieneusi是先前被归类为原生动物的微孢子虫。在影响人类健康的14种物种中，E. Bieneusi是临床上最重要的新兴肠道病原体，它感染了大多数哺乳动物物种的胃肠道，并且是慢性腹泻，患有艾滋病毒/艾滋病患者的慢性腹泻，浪费和胆管炎的主要原因。与缺乏体外实验室繁殖方法以及孢子来源有限的技术困难相关的，在理解对这种新兴病原体的生物学，发病机理和保护性免疫反应方面的进展非常缓慢。这些小组最近在很大程度上克服了这些功能，这为该应用程序提供了动力。该应用的长期目标是增强我们对E. Bieneusi保护性免疫涉及的机制的理解。该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中致命的感染。我们的初步数据表明，IFN-gamma是提供对生物E. bieneusi感染的初始耐药性的重要组成部分。 E Bieneusi对细胞活化的分子基础的研究，包括启动这种初始抗性的先天免疫受体的表征。本应用的目标是确定负责在生物息肉内感染期间启动先天免疫的特定细胞受体和衔接子蛋白，并确定在上皮细胞感染期间受宿主免疫系统调节哪些IFN-GAMMA依赖性成分。 TLR在先天免疫和IFN-GAMMA调控基因中的作用将在这种感染中必不可少。具体目的是： 1。检查可能与先天免疫感染有关的Bieneusi特异性IFN-GAMMA调控基因的表达。 2。确定Toll样受体（TLR）/MYD88信号通路的作用，在诱导IFN-GAMMA中的作用， 响应生物大肠杆菌感染。阐明先天免疫调节的机理基础将使人们更好地理解对生物大肠杆菌感染的抗性。此外，先天免疫会显着影响对许多感染的获得免疫的产生。因此，拟议的研究将构成一个基础，以建立进一步的研究，以研究先天免疫的调节如何影响获得这种新兴感染的免疫力。