Viral infections and celiac disease pathogenesis

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和诱导乳糜泻（CD）的机制。越来越多的人认识到病毒感染是复杂炎性疾病发病机制中的促成因素。然而，人们对病毒引起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，具有自身免疫组分，其特征在于仅在具有HLA DQ 2或DQ 8等位基因的麸质暴露者中发生的炎性抗麸质免疫应答。知识上的差距妨碍了对高危个体的精确识别以及预防和治疗CD的新方法的开发。大约45%的美国人口表达DQ 2或DQ 8分子，但只有1%的人口发展这种疾病。这一观察结果表明，其他环境因素有助于疾病的诱导。虽然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由病毒感染和1型干扰素的加工介导。呼肠孤病毒是研究CD增强病毒感染的特别有吸引力的模型。这些病毒是属于呼肠孤病毒科的人dsRNA病毒，其与增加的CD发病率相关。呼肠孤病毒感染鼠肠道，并且可以被遗传操纵以鉴定自身免疫宿主应答的病毒决定簇。这一建议的中心假设是，对病毒感染的反应构成了一种替代方案， IL-15信号通路或效应子应答，通过对口服抗原（Ag）的免疫应答失调导致CD。这一假设将在两个整合良好的具体目标进行测试。在具体目标1中，我们将通过使用从两种在LOT能力上不同的充分表征的呼肠孤病毒株产生的重组病毒来鉴定影响LOT中涉及的病毒-宿主相互作用的病毒决定簇。在具体目标2中，我们将通过表征呼肠孤病毒感染在HLA-DQ 8 tg小鼠中诱导潜在CD的能力，以及在定义病毒诱导CD的转录特征的同时确立A型和B型CD的证据，来确立病毒诱导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。该项目汇集了三个国际公认的PI，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提高对病毒感染如何导致复杂疾病发展的理解。此外，通过剖析由不同刺激触发的CD病理学中涉及的途径，我们将个性化CD并基于特定CD机制促进预防和治疗。

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.