Viral infections and celiac disease pathogenesis

病毒感染和乳糜泻发病机制

• 批准号: 8690416
• 负责人: TERENCE S. DERMODY
• 金额: $ 68.95万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-20 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690416
• 关键词: Alleles; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Autoimmune Process; Biological; CD3D gene; Caring; Celiac Disease; Cells; Clinical; Complex; Data; Dendritic Cells; Development; Disease; Double Stranded RNA Virus; Elements; Environmental Risk Factor; Epithelium; Genes; Genetic; Genomics; Gluten; Goals; HLA-DQ8 antigen; Human; Human Virus; Immune; Immune System Diseases; Immune response; Immunity; Immunology; Incidence; Individual; Induction of Apoptosis; Infection; Inflammatory; Interferons; Interleukin-15; Intestinal Diseases; Intestines; Knowledge; Lamina Propria; Lead; Link; Mediating; Mediator of activation protein; Microarray Analysis; Mus; Oral; Pathogenesis; Pathology; Pathway interactions; Patients; Persons; Phenotype; Population; Prevalence; Prevention; Property; Reassortant Viruses; Reoviridae; Reoviridae Infections; Reovirus; Research; Risk; Shapes; Signal Transduction; Stimulus; Study models; Systems Biology; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenic Mice; Villous Atrophy; Viral; Viral Genes; Virus; Virus Diseases; Wild Type Mouse; base; candidate identification; disability; feeding; insight; mouse model; novel; oral tolerance; overexpression; prevent; public health relevance; research study; response; tool; virology; virus host interaction

DESCRIPTION (provided by applicant): The central goal of the proposed research is to determine mechanisms by which viral infections lead to loss of oral tolerance and induce celiac disease (CD). Viral infections are increasingly recognized as contributing factors in the pathogenesis of complex inflammatory diseases. However, little is known about the biological features that enable a virus to provoke development of inflammatory disorders. CD is a complex T cell- mediated intestinal disorder with an autoimmune component characterized by an inflammatory anti-gluten immune response that occurs exclusively in gluten-exposed persons with HLA DQ2 or DQ8 alleles. Gaps in knowledge preclude precise identification of at-risk individuals and development of new ways to prevent and treat CD. Approximately 45% of the U.S. population expresses DQ2 or DQ8 molecules, yet only 1% of the population develops the disease. This observation indicates that additional environmental factors contribute to disease induction. Although a common feature of CD is loss of oral tolerance (LOT) to gluten, we have new evidence that CD is a heterogeneous disorder consisting of two main types. Type A CD is mediated by IL-15, whereas Type B CD is mediated by viral infections and elaboration of type-1 interferons. Reoviruses are particularly attractive models for studies of CD-potentiating viral infections. These viruses are human dsRNA viruses that belong to the Reoviridae, which are associated with an increased CD incidence. Reoviruses infect the murine intestine and can be genetically manipulated to identify viral determinants of autoimmune host responses. The central hypothesis of this proposal is that responses to viral infections constitute an alternative pathway to IL-15 signaling or effector responses that leads to CD by dysregulating immune responses to oral antigen (Ag). This hypothesis will be tested in two well-integrated specific aims. In Specific Aim 1, we will identify viral determinants that shape the virus-host interaction implicated in LOT by using reassortant viruses generated from two well-characterized reovirus strains that differ in LOT capacity. In Specific Aim 2, we will establish evidence for virus-induce CD by characterizing the capacity of reovirus infection to induce potential CD in HLA-DQ8 tg mice as well as establishing evidence for a Type A and Type B CD while defining transcriptional signatures for virus-induced CD. Insights gained from these studies will enable identification of candidate pathways for virus-induced Type B CD. This project brings together three internationally recognized PIs with complementary expertise in CD, mucosal immunology, virology, and systems biology. Knowledge gained through these efforts will enhance an understanding of how viral infections lead to development of complex disorders. Furthermore, by dissecting pathways involved in CD pathology triggered by different stimuli, we will personalize CD and promote prevention and treatment based on specific CD mechanisms.

描述（由申请人提供）：拟议研究的核心目标是确定病毒感染导致口腔耐受性丧失并诱导乳糜泻（CD）的机制。病毒感染越来越多地被认为是复杂炎症性疾病发病机理中的促成因素。但是，对使病毒引起炎症性疾病发展的生物学特征知之甚少。 CD是一种复杂的T细胞介导的肠道疾病，具有自身免疫成分，其特征在于炎性抗lut蛋白免疫反应，该反应仅发生在具有HLA DQ2或DQ8等位基因的麸质暴露的人中。知识的差距排除了高危个人的精确识别，并开发了预防和治疗CD的新方法。大约45％的美国人口表达了DQ2或DQ8分子，但只有1％的人口发展为疾病。该观察结果表明，其他环境因素导致疾病诱导。尽管CD的一个共同特征是对面筋的口服耐受性丧失（批次），但我们有新的证据表明CD是由两种主要类型组成的异质性疾病。 A型CD由IL-15介导，而B型CD是由病毒感染和1型干扰素阐述介导的。肠道病毒是用于研究CD抑制病毒感染的特别有吸引力的模型。这些病毒是属于依维氏病的人DSRNA病毒，与CD发病率增加有关。肠道病毒感染鼠肠，可以通过遗传操纵来鉴定自身免疫宿主反应的病毒决定因素。该提议的中心假设是对病毒感染的反应构成了一种替代 通往IL-15信号传导或效应子响应的途径，通过对口服抗原（AG）的免疫反应失调而导致CD。该假设将以两个整合的特定目的进行检验。在特定的目标1中，我们将通过使用由两个特征良好的综合型孢子病毒菌株产生的重新成分病毒来塑造与LOT有关的病毒宿主相互作用的病毒决定因素，这些病毒含量有所不同。在特定的目标2中，我们将通过表征葡萄病毒感染在HLA-DQ8 TG小鼠中诱导潜在CD的能力以及为A型A型和B型CD的证据建立证据，同时确定病毒诱导的CD的转录特征，从而为病毒诱导CD建立证据。从这些研究中获得的见解将使病毒诱导的B型CD的候选途径鉴定。该项目汇集了三个国际认可的PI，具有CD，粘膜免疫学，病毒学和系统生物学方面的互补专业知识。通过这些努力获得的知识将增强对病毒感染如何导致复杂疾病发展的理解。此外，通过解剖不同刺激触发的CD病理学的途径，我们将个性化CD并基于特定的CD机制促进预防和治疗。