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）：拟议研究的中心目标是确定病毒感染导致口服耐受性丧失并诱发乳糜泻（CD）的机制。人们越来越多地认识到病毒感染是复杂炎症性疾病发病机制的影响因素。然而，人们对病毒引发炎症性疾病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，其特征是炎症性抗麸质免疫反应，仅发生在具有 HLA DQ2 或 DQ8 等位基因的麸质暴露人群中。知识差距阻碍了对高危个体的精确识别以及预防和治疗克罗恩病的新方法的开发。大约 45% 的美国人表达 DQ2 或 DQ8 分子，但只有 1% 的人患上这种疾病。这一观察表明，额外的环境因素有助于疾病的诱发。尽管 CD 的一个共同特征是对麸质的口服耐受性 (LOT) 丧失，但我们有新的证据表明 CD 是一种异质性疾病，由两种主要类型组成。 A 型 CD 由 IL-15 介导，而 B 型 CD 由病毒感染和 1 型干扰素的产生介导。呼肠弧病毒是研究 CD 增强病毒感染特别有吸引力的模型。这些病毒是人类 dsRNA 病毒，属于呼肠孤病毒科，与 CD 发病率增加有关。呼肠孤病毒感染小鼠肠道，可通过基因操作来识别自身免疫宿主反应的病毒决定因素。该提案的中心假设是对病毒感染的反应构成了另一种选择 IL-15 信号传导或效应反应的通路，通过调节对口腔抗原 (Ag) 的免疫反应而导致 CD。这一假设将在两个整合良好的具体目标中得到检验。在具体目标 1 中，我们将通过使用从 LOT 容量不同的两种特征良好的呼肠孤病毒株生成的重配病毒来确定 LOT 中涉及的病毒与宿主相互作用的病毒决定因素。在具体目标 2 中，我们将通过表征呼肠孤病毒感染在 HLA-DQ8 tg 小鼠中诱导潜在 CD 的能力，以及建立 A 型和 B 型 CD 的证据，同时定义病毒诱导 CD 的转录特征，来建立病毒诱导 CD 的证据。从这些研究中获得的见解将能够识别病毒诱导的 B 型 CD 的候选途径。该项目汇集了三位国际公认的 PI，他们在 CD、粘膜免疫学、病毒学和系统生物学方面具有互补的专业知识。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，通过剖析不同刺激引发CD病理的通路，我们将个性化CD，并基于特定的CD机制促进预防和治疗。