Regulation of Innate Immunity to Enterocytozoon bieneusi Infection

描述（由申请人提供）：本R21申请是对RFA-AI-05-042关于B类病原体先天免疫的回应，其中bieneusenterocytozoon bieneusi是一种微孢子虫，以前被归类为原生动物。在影响人类健康的14种病原菌中，比氏肠杆菌是临床上最重要的新兴肠道病原体，可感染大多数哺乳动物的胃肠道，是导致HIV/AIDS患者、营养不良儿童和接受免疫抑制治疗的患者慢性腹泻、消瘦和胆管炎的主要原因。由于缺乏体外实验室繁殖方法以及孢子来源有限，技术上的困难导致对这种新出现的病原体的生物学、发病机制和保护性免疫反应的了解进展非常缓慢。我们的小组最近在很大程度上克服了这些问题，这为这一应用提供了动力。这项应用的长期目标是加强我们对白氏肠杆菌保护性免疫机制的理解。这一信息对于开发有效的免疫治疗方法至关重要，可以帮助解决免疫缺陷个体的致命感染。我们的初步数据表明，ifn - γ是提供对贝氏肠杆菌感染的初始抗性的重要组成部分。目前尚不清楚白氏杆菌激活细胞的分子基础，包括启动这种初始抗性的先天免疫受体的特征。本应用程序的目的是鉴定在双胞梭菌感染期间负责启动先天免疫的特定细胞受体和衔接蛋白，并确定在上皮细胞感染期间宿主免疫系统调节哪些ifn - γ依赖性成分。tlr在先天免疫中的作用和ifn - γ调节基因在这种感染的背景下是必不可少的，将被调查。具体目标是：

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.