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.

项目概要/摘要 鼻病毒 (RV) 感染经常引起感冒，但这些病毒也会导致下呼吸道疾病 幼儿和老年人的感染，以及 50-90% 的哮喘恶化。此外，RV 相关 学龄前儿童的喘息疾病是罹患哮喘的重要危险因素。缺乏具体的 对更严重的右心室疾病和哮喘恶化的治疗是一个未得到满足的主要医疗需求。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，因为这是重感冒 导致哮喘患者病情加重，并增加哮喘患者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）强烈影响严重程度 与 RV 感染相关的疾病。我们的高度互动项目由 2 个项目和 2 个核心组成，将 定义对严重病毒性呼吸道疾病（VRI）的易感性与抵抗力的机制。临床上 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诞生 旨在调查农场暴露、免疫成熟以及传染性和过敏性之间联系的队列 呼吸道疾病。该队列现已全部注册，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 农业微生物暴露和生命早期微生物定植的独特模式改变了先天 和 T 调节的发展，从而预防 VRI 和过敏性疾病。为了测试这个 假设，我们将跟踪当前 WISC 参与者的年龄至 4-8 岁，并招募更多农场和非农场人员 新生儿（50 名/组）将使用新技术进行监测，以更好地定义生命早期的微生物 暴露和免疫发育。我们与威斯康星州阿米什人建立了关系 社区的过敏性疾病发病率非常低，新的社区中将包括 50 名阿米什新生儿 新兵。项目 II 将重点关注 RV C 物种 (RV-C) 和钙粘蛋白相关蛋白 3 之间的相互作用 (CDHR3) 对宿主气道上皮细胞的影响。 RV-C 与更严重的疾病和严重恶化有关 哮喘，但人们对 RV-C 的发病机制知之甚少。我们最近的工作极大地推进了这一事业 开发新的分子工具、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。在当前的项目 II 提案中，我们将进行 进一步定义 RV-C 结构、与 CDHR3 相互作用的生物化学以及遗传的实验 以及调节CDHR3的亚细胞表达和功能的生化机制。 了解病毒衣壳以及与 CDHR3 的相互作用将为小分子提供两个新靶点 RV-C 抗病毒药。最终，这些信息将带来治疗和预防 VRI 的新策略 和儿童呼吸道过敏。