Viral and Environmental Determinants of Rhinovirus Illness Severity

项目摘要/摘要 鼻病毒(RV)感染经常会导致感冒，但这些病毒也会导致下呼吸道 儿童和老年人的感染，以及50%-90%的哮喘恶化。此外，房车关联 学龄前儿童的喘息性疾病是发展为哮喘的强烈风险因素。缺乏具体的 治疗更严重的RV疾病和哮喘恶化是一个主要的未得到满足的医疗需求。什么 决定由轮状病毒感染引起的疾病的严重程度？这是一个关键问题，因为它是重感冒 会导致哮喘患者病情加重，并增加哮喘复发和哮喘的风险 学龄前儿童。我们认为与病毒(RV种类)、宿主(RV受体遗传学、 先天免疫反应)和环境(农场微生物群)强烈影响疾病的严重程度 与RV感染相关的疾病。我们由2个项目和2个核心组成的高度互动计划将 明确对严重病毒性呼吸道疾病(VRI)的易感性与抵抗力的机制。临床部 该计划的核心是威斯康星州婴儿研究队列(WISC)(项目I)，这是一个独特的奶牛场出生 旨在调查农场暴露、免疫成熟以及传染性和过敏性之间的联系的队列 呼吸道疾病。队列现在已经完全登记，我们的初步数据表明，农场暴露在 减少VRI和特应性皮炎，这是哮喘的两个重要危险因素。我们现在假设 农业微生物暴露与先天生命早期微生物定植的独特模式 以及T调节的发展，这导致了对VRI和过敏性疾病的保护。为了测试这一点 假设，我们将跟随现有的WISC参与者到4-8岁，并招募更多的农场和非农场 新生儿(50人/组)，将使用新技术进行监测，以更好地定义早期生命微生物 暴露和免疫发展。我们已经和威斯康星州的阿米什人建立了关系 社区，他们的过敏性疾病的比率非常低，并将包括50名阿米什新生儿在新的 新兵。项目II将重点研究RV C物种(RV-C)与钙粘蛋白相关蛋白-3之间的相互作用 (CDHR3)表达于宿主呼吸道上皮细胞。RV-C与更严重的疾病和严重的 哮喘，但对RV-C的发病机制知之甚少。我们最近的工作极大地推动了这项事业 开发新的分子工具、培养和生产技术，鉴定第一个细胞表面受体， 确定RV-C的三维分子结构。在目前的项目II提案中，我们将进行 进一步确定RV-C结构的实验，与CDHR3相互作用的生化，以及遗传 以及调控CDHR3亚细胞表达和功能的生化机制。 了解病毒衣壳及其与CDHR3的相互作用将为小分子研究提供两个新的靶点 RV-C抗病毒药物。最终，这些信息将导致预防VRI的新的治疗策略 和儿童的呼吸道过敏。

PROJECT SUMMARY/ABSTRACT Rhinovirus (RV) infections frequently cause colds, and yet these viruses also contribute to lower respiratory infections in young children and the elderly, and to 50-90% of asthma exacerbations. Moreover, RV associated wheezing illnesses in preschoolers are strong risk factors for developing asthma. The lack of specific treatments for more severe RV illnesses and exacerbations of asthma is a major unmet medical need. What determines the severity of illness caused by RV infections? This is a key question, since it is the severe colds that cause exacerbations in patients with asthma and increase the risk of recurrent wheeze and asthma in preschoolers. We propose that factors related to the virus (RV species), host (RV receptor genetics, innate immune response), and environment (the farm microbiome) strongly influence the severity of illness associated with RV infection. Our highly interactive program consisting of 2 projects and 2 cores will define mechanisms of susceptibility vs. resistance to severe viral respiratory illnesses (VRI). The clinical centerpiece of the program is the Wisconsin Infant Study Cohort (WISC) (Project I), a unique dairy farm birth cohort designed to investigate links between farm exposures, immune maturation, and infectious and allergic respiratory disease. The cohort is now fully enrolled, and our preliminary data suggest that farm exposures reduce both VRI and atopic dermatitis, two important risk factors for asthma. We now hypothesize that farming microbial exposures and unique patterns of microbial colonization in early life alter of innate and T regulatory development, which lead to protection from VRI and allergic diseases. To test this hypothesis, we will follow current WISC participants to age 4-8 years, and recruit additional farm and non-farm newborns (50/group) who will be monitored with new technologies to better define early life microbial exposures and immune development. We have established relationships with the Wisconsin Amish community, who have very low rates of allergic diseases, and will include 50 Amish newborns in the new recruits. Project II will focus on interactions between the RV C species (RV-C) and cadherin related protein-3 (CDHR3) on host airway epithelial cells. RV-C are linked to more severe illnesses and severe exacerbations of asthma, but little is known about RV-C pathogenesis. Our recent work has greatly advanced this cause by developing novel molecular tools, culture and production techniques, identifying the first cell surface receptor, and determining the 3D molecular structure for RV-C. In the current proposal for Project II, we will conduct experiments to further define RV-C structure, the biochemistry of interactions with CDHR3, and genetic and biochemical mechanisms regulating the subcellular expression and function of CDHR3. Understanding the virus capsid and interactions with CDHR3 would provide two new targets for small molecule RV-C antivirals. Ultimately, this information will lead to new strategies for the treatment of prevention of VRI and respiratory allergies in children.