Viral and Environmental Determinants of Rhinovirus Illness Severity

鼻病毒疾病严重程度的病毒和环境决定因素

• 批准号: 10397758
• 负责人: James E. Gern
• 金额: $ 12.21万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-21 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397758
• 关键词: 3-Dimensional; Address; Adult; Affect; Age; Allergic; Allergic Disease; Allergic inflammation; Amish; Antiviral Agents; Antiviral Response; Asthma; Atopic Dermatitis; Bacteria; Biochemical; Biochemistry; Birth; C cadherin; Cadherins; Capsid; Cell Surface Receptors; Cell physiology; Cells; Child; Childhood; Chronic Obstructive Pulmonary Disease; Clinical; Cohort Studies; Common Cold; Communities; Data; Detection; Development; Disease; Elderly; Enrollment; Environment; Epithelial; Epithelial Cells; Exposure to; Farm; Genetic; Goals; Growth; Hospitalization; Hypersensitivity; Immune; Immune response; Infant; Infection; Inflammatory; Innate Immune Response; Interferons; Knowledge; Lead; Life; Link; Lower Respiratory Tract Infection; Medical; Microbe; Molecular; Molecular Structure; Molecular Virology; Monitor; Mononuclear; Morbidity - disease rate; Natural Immunity; Newborn Infant; Participant; Pathogenesis; Patients; Pattern; Population; Predisposition; Prevention; Production; Program Research Project Grants; Proteins; Recurrence; Regulatory T-Lymphocyte; Resistance; Respiratory Disease; Rhinovirus; Rhinovirus infection; Risk; Risk Factors; Services; Severities; Severity of illness; Shapes; Societies; Structure; Symptoms; Techniques; Testing; Viral; Virulence; Virus; Virus Diseases; Virus Replication; Wheezing; Wisconsin; Work; airway epithelium; airway obstruction; asthma exacerbation; burden of illness; chemokine; chronic respiratory disease; cofactor; cohort; commensal bacteria; community acquired pneumonia; cost; design; early life exposure; experimental study; follow-up; improved; infancy; microbial; microbial colonization; microbiome; neonate; neutrophil; new technology; novel; novel therapeutic intervention; pathogen; pathogenic bacteria; pediatric patients; programs; receptor; recruit; respiratory; respiratory microbiome; respiratory morbidity; respiratory virus; response; small molecule; tool; treatment strategy

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.

项目摘要/摘要 鼻病毒（RV）感染经常引起感冒，但这些病毒也导致下呼吸道 幼儿和老年人的感染，哮喘患病的50-90％。此外，RV相关 学龄前儿童中的喘息疾病是患哮喘的强烈危险因素。缺乏具体 治疗更严重的RV疾病和哮喘加剧的治疗是一种主要的未满足医疗需求。什么 确定RV感染引起的疾病的严重程度？这是一个关键问题，因为这是严重的感冒 这会导致哮喘患者加剧，并增加复发性喘息和哮喘的风险 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 定义易感性与对严重病毒呼吸道疾病（VRI）的抵抗力的机制。临床 该计划的核心是威斯康星州婴儿研究队列（WISC）（项目I），这是一个独特的奶牛场出生 旨在研究农场暴露，免疫成熟与传染性和过敏性之间的联系 呼吸道疾病。该队列现在已完全注册，我们的初步数据表明农场暴露 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 耕种微生物暴露和微生物定植的独特模式在早期生活改变 和调节性开发，可保护VRI和过敏性疾病。测试这个 假设，我们将跟随当前的WISC参与者到4-8岁，并招募其他农场和非农场 新生儿（50/组）将接受新技术的监控，以更好地定义早期生命微生物 暴露和免疫发育。我们已经与威斯康星州阿米什人建立了关系 社区，过敏性疾病的发生率非常低，并且将包括50名阿米什人新生儿 新兵。项目II将重点关注RV C物种（RV-C）和Cadherin相关蛋白质-3之间的相互作用 （CDHR3）在宿主气道上皮细胞上。 RV-C与更严重的疾病和严重加重有关 哮喘，但对RV-C发病机理知之甚少。我们最近的工作大大推动了这一原因 开发新型的分子工具，培养和生产技术，识别第一个细胞表面受体， 并确定RV-C的3D分子结构。在当前关于项目II的建议中，我们将进行 实验以进一步定义RV-C结构，与CDHR3相互作用的生物化学和遗传 以及调节CDHR3亚细胞表达和功能的生化机制。 了解病毒衣壳和与CDHR3的相互作用将为小分子提供两个新目标 RV-C抗病毒药。最终，这些信息将导致治疗预防VRI的新策略 和儿童的呼吸过敏。