Transgenic Mouse Model for the Common Cold

描述(申请人提供)：病毒性呼吸道感染是全世界所有年龄段的人急性发病的最常见原因。在旺季所有急性呼吸道感染中，仅小核糖核酸病毒一项就占所有急性呼吸道感染的80%，是限制活动和医生咨询的主要原因。尽管小核糖核酸病毒引起的普通感冒病程一般是良性的，但它是严重呼吸系统疾病急性加重的主要罪魁祸首，例如支气管哮喘或慢性阻塞性肺疾病。原发微小病毒呼吸道感染或继发性肺部疾病加重的机制尚不完全清楚。此外，目前还没有特效的抗病毒化疗。在致病机制研究和抗病毒药物开发方面取得进展的一个主要障碍是缺乏实用的普通感冒动物模型。一般来说，对发病机制和药理测试的研究依赖于志愿者的故意感染。我们建立了转人细胞间黏附分子-1(hICAM-1)基因的小鼠，它在呼吸道上皮细胞中表现出类似于人类的hICAM-1表达。这些小鼠原则上容易感染绝大多数微小核糖核酸病毒，这种病毒识别hICAM-1是一种细胞受体。本项目旨在通过产生具有呼吸趋向性的小核糖核酸病毒来建立普通感冒小鼠模型，该病毒能够在hICAM-1转基因小鼠的呼吸道内繁殖并引发特征性病变和宿主反应。我们的研究旨在为普通感冒建立一个实用的小动物模型，普通感冒是全球肺部疾病和相关医疗保健支出的主要原因。这种疾病模型将提供更好的机会来揭示病毒呼吸道感染的机制，并测试新的治疗方法，使有潜在肺部疾病恶化风险的患者受益。

DESCRIPTION (provided by applicant): Viral respiratory tract infections are the most common cause of acute morbidity in individuals of all ages worldwide. Picornaviruses alone are responsible for ~80% of all acute respiratory infections during peak season and are a major cause for restricted activity and physician consultation. Despite the generally benign course of the common cold caused by picornaviruses, it is the main culprit for acute exacerbation of serious respiratory system disorders, for example bronchial asthma or chronic obstructive pulmonary disease. The mechanisms of primary picornaviral respiratory tract infection or secondary exacerbation of pulmonary disease are not fully understood. Moreover, no specific anti-viral chemotherapy is available. A major impediment to advances in research of pathogenic mechanisms and anti-viral drug development is the absence of a practical animal model for the common cold. Generally, studies of pathogenesis and pharmacologic testing rely on deliberate infection of volunteers. We generated mice transgenic for the human intercellular adhesion molecule-1 (hICAM-1) gene, which exhibit hICAM-1 expression in respiratory epithelium similar to humans. These mice in principle are susceptible to infection with the vast majority of picornaviruses, which recognize hICAM-1 as a cellular receptor. This project aims to establish a murine model for the common cold by generating picornaviruses with respiratory tropism capable of propagating and eliciting characteristic lesions and host responses in the respiratory tract of hICAM-1 transgenic mice. Our research intends to generate a practical small animal model for the common cold, a major cause for pulmonary illness and associated health care expenditure worldwide. This disease model would provide far improved opportunities to unravel mechanisms of viral respiratory tract infection and to test new therapeutic approaches benefiting patients at risk from exacerbation of underlying pulmonary disease.