Viral and Environmental Determinants of Rhinovirus Illness Severity

项目总结/摘要 鼻病毒（RV）感染经常引起感冒，但这些病毒也有助于下呼吸道感染。 感染的幼儿和老年人，和50-90%的哮喘急性发作。此外，RV相关 学龄前儿童的喘息性疾病是发生哮喘的重要危险因素。缺乏具体 更严重的RV疾病和哮喘恶化的治疗是一个主要的未满足的医疗需求。什么 决定RV感染引起的疾病的严重程度？这是一个关键问题，因为它是严重的感冒， 导致哮喘患者病情加重，并增加喘息和哮喘复发的风险， 学龄前儿童我们提出与病毒（RV物种）、宿主（RV受体遗传学， 先天免疫反应）和环境（农场微生物组）强烈影响 与RV感染有关的疾病。我们的高度互动的计划包括2个项目和2个核心将 定义对严重病毒性呼吸道疾病（VRI）的易感性与耐药性机制。临床 该计划的核心是威斯康星州婴儿研究队列（WISC）（项目I），一个独特的奶牛场出生 队列研究旨在调查农场暴露、免疫成熟与传染性和过敏性之间的联系 呼吸道疾病该队列现已全部入组，我们的初步数据表明， 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 农业微生物暴露和微生物定植的独特模式在生命早期改变先天 和T调节的发展，这导致对VRI和过敏性疾病的保护。为了验证这一 假设，我们将跟踪目前WISC参与者到4-8岁，并招募更多的农场和非农场 新生儿（50/组），将采用新技术进行监测，以更好地确定生命早期微生物 暴露和免疫发育。我们已经和威斯康星州的阿米什人建立了关系 社区，谁有过敏性疾病的发病率非常低，并将包括50个阿米什新生儿在新的 新兵项目II将重点关注RV C种类（RV-C）和钙粘蛋白相关蛋白-3之间的相互作用 （CDHR 3）对宿主气道上皮细胞的作用。RV-C与更严重的疾病和严重恶化有关， 哮喘，但对RV-C的发病机制知之甚少。我们最近的工作大大推进了这一事业， 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， 并确定RV-C的三维分子结构。在项目II的当前提案中，我们将进行 进一步确定RV-C结构的实验，与CDHR 3相互作用的生物化学，以及遗传学， 以及调节CDHR 3的亚细胞表达和功能的生化机制。 了解病毒衣壳和与CDHR 3的相互作用将为小分子药物提供两个新的靶点。 RV-C抗病毒药物最终，这些信息将导致新的战略，为预防VRI的治疗 和儿童呼吸道过敏。

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.