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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

基本信息

批准号：
7244041
负责人：
SAUL r TZIPORI
金额：
$ 23.9万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7244041
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Adaptor Signaling Protein Affect Antigen-Presenting Cells Biology CXCL10 gene CXCL9 gene Categories Cells Child Cholangitis Chronic Cryptosporidium parvum Cultured Cells Data Dendritic Cells Development Dexamethasone Diagnostic Diarrhea Enteral Enterocytozoon bieneusi Epithelial Cells Essential Genes Feces Foundations Gastrointestinal tract structure Gene Expression Profiling Generations Genes Goals Guanosine Triphosphate Phosphohydrolases Health Host resistance Human Immune Immune response Immune system Immunity Immunologic Receptors Immunotherapeutic agent In Vitro Individual Infection Interferon Type II Interferons Interleukin-12 Intestinal Mucosa Intestines Investigation Knock-out Knockout Mice Laboratories Lamina Propria Lead Messenger RNA Methods Microsporidia Microsporidium Molecular Monoclonal Antibodies Mus Mycobacterium avium Mycoses Natural Immunity Natural Killer Cells Numbers Outcome Parasites Pathogenesis Patients Personal Satisfaction Play Polymeric Immunoglobulin Receptors Population Predisposition Prevalence Production Protein Family Protozoa RANTES RNA Rate Regulation Reproduction spores Resistance Resistance to infection Reverse Transcriptase Polymerase Chain Reaction Rodent Role SCID Mice Signal Pathway Signal Transduction Site Source TLR2 gene TLR4 gene Therapeutic immunosuppression Thinking Time Toll-like receptors Transcriptional Activation Up-Regulation Virus Diseases acquired immunity antimicrobial base cell type chemokine clinical Diagnosis cytokine design enteric pathogen in vivo intraepithelial member microbial microorganism antigen mouse model pathogen preconditioning prevent receptor response tool wasting

项目摘要

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RFA-AI-05 - 042关于对B类病原体的天然免疫力的回应，其中比氏肠细胞虫是一种先前归类为原生动物的微孢子虫。在影响人体健康的14种寄生虫中，E.在临床上，比纽氏菌是感染大多数哺乳动物物种的胃肠道的最重要的新兴肠道病原体，并且是HIV/AIDS患者、营养不良儿童和接受免疫抑制治疗的患者中慢性腹泻、消瘦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相关的技术困难，导致对这种新兴病原体的生物学，发病机理和保护性免疫反应的理解进展非常缓慢。这些问题最近在很大程度上被我们的小组克服了，这为这一应用提供了动力。本申请的长期目标是增强我们对E.保护性免疫这些信息对于开发有效的免疫方法至关重要，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-γ是提供对大肠杆菌初始抵抗力的重要成分。毕氏菌感染调查的细胞活化的分子基础，由E bieneusi，包括先天性免疫受体的特性，启动这种初始的阻力是未知的。本申请的目的是鉴定在大肠杆菌感染过程中负责启动先天免疫的特异性细胞受体和衔接蛋白。bieneusi感染，并确定哪些IFN-γ依赖性组分在上皮细胞感染期间受宿主免疫系统调节。TLR在先天免疫中的作用和IFN-γ调节的基因在这种感染的背景下是必不可少的，将进行调查。具体目标是： 1.检测E.细菌特异性IFN-γ调节基因可能参与对感染的先天免疫。 2.为了确定Toll样受体（TLR）/MyD88信号通路在IFN-γ诱导中的作用，响应E.毕氏菌感染阐明天然免疫调节的机制基础将有助于更好地理解大肠杆菌的抗性。毕氏菌感染此外，先天免疫显著影响对许多感染的获得性免疫的产生。因此，拟议的研究将为进一步研究先天免疫的调节如何影响对这种新兴感染的获得性免疫奠定基础。