Regulation of Innate Immunity to Enterocytozoon bieneusi Infection

描述(申请人提供)：本R21申请是对RFA-AI-05-042关于对B类病原体的先天免疫的回应，其中肠道细胞寄生虫是一种以前被归类为原生动物的微孢子虫。在影响人类健康的14种病原菌中，比埃希氏菌是临床上出现的最重要的肠道病原体，感染大多数哺乳动物的胃肠道，是艾滋病毒/艾滋病患者、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。缺乏实验室体外繁殖方法以及有限的孢子来源带来的技术困难，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。我们的团队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。这一应用的长期目标是加强我们对比氏艾美耳球虫保护性免疫机制的了解。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患者的致命感染。我们的初步数据表明，干扰素-γ是提供对贝氏艾美耳球虫感染的初始抵抗力的重要成分。对E bieneusi激活细胞的分子基础的研究，包括启动这种初始抵抗力的先天免疫受体的特征尚不清楚。这项应用的目的是确定在感染贝氏艾美耳球虫过程中负责启动天然免疫的特定细胞受体和适配器蛋白，并确定在上皮细胞感染过程中哪些干扰素-γ依赖成分受到宿主免疫系统的调节。TLRs在先天性免疫中的作用以及在这种感染背景下必不可少的干扰素-伽马调节基因将被调查。具体目标是： 1.检测毕氏艾美耳球虫特异的干扰素-γ调节基因的表达，这些基因可能与先天免疫感染有关。 2.探讨Toll样受体(TLR)/MyD88信号通路在干扰素-γ诱导中的作用。 以应对E.bieneusi的感染。阐明天然免疫调节的机制基础将有助于更好地理解对贝氏艾美耳球虫感染的抵抗力。此外，先天免疫显著影响对许多感染的获得性免疫的产生。因此，拟议的研究将成为进一步研究先天免疫调节如何影响对这种新出现感染的获得性免疫的基础。

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.