Development of the Cotton Rat Model of Rhinovirus Infection and Disease

描述（由申请人提供）：人鼻病毒（HRV）是感冒和流感样疾病的最常见原因。此外，HRV感染与相当严重的疾病有关，如哮喘加重、儿童喘息性疾病和慢性阻塞性肺病（COPD）。鼻病毒感染的发病率和死亡率相当高，每年造成数十亿美元的医疗费用。尽管该问题的重要性，但目前没有有效预防HRV感染或治疗HRV相关疾病的方法。在从小鼠到猴子的许多物种中开发HRV感染的小动物模型的尝试都失败了，因此严重阻碍了针对HRV感染的机制研究和疫苗和治疗剂的开发。与实验室小鼠和大鼠不同，棉鼠（Sigmodon hispidus）对人类病毒感染表现出独特的易感性，并已成为许多人类呼吸道病原体的首选模型，包括呼吸道合胞病毒（RSV）、流感病毒（A和B）、腺病毒（几种血清型）、副流感病毒（3型）和麻疹。本项目的长期目标是利用棉鼠建立一种可靠的HRV感染模型。基于棉鼠对多种人类病毒的敏感性以及我们自己的初步研究表明，鼻内感染HRV 16会导致棉鼠呼吸道病理学，我们提出：首先，通过以下方法描述棉鼠中HRV 16急性感染的特征：（a）定义HRV 16感染的动力学;（B）选择可用于跟踪急性疾病的临床参数;（c）描述HRV-16诱导的上呼吸道和下呼吸道病理;和（d）定义由HRV-16感染引起的细胞因子和趋化因子的表达。其次，我们将集中在表征的保护性免疫反应所产生的HRV 16感染的棉鼠。一个强大的研究团队已经组建，结合了广泛的专业知识，在使用棉鼠和强大的病毒学能力。如果成功，拟议的研究将导致 有价值的实验资源，用于测试针对“普通感冒”的疫苗和疗法。

DESCRIPTION (provided by applicant): Human rhinoviruses (HRVs) are the most common cause of colds and flu-like illnesses. In addition, HRV infections are associated with disease of considerable severity, such as exacerbation of asthma, wheezing illness in children, and chronic obstructive pulmonary disease (COPD). The morbidity and mortality attributable to rhinovirus infection is considerable and results in billions of dollars of health care cost every year. Despit the significance of the problem, no effective prevention of HRV infection or treatment of HRV-associated disease is currently available. Attempts to develop a small animal model of HRV infection in many species, from mice to monkeys, have failed, thus severely hampering mechanistic studies and the development of vaccines and therapeutics against HRV infection. Unlike the laboratory mouse and rat, the cotton rat (Sigmodon hispidus) exhibits a unique susceptibility to infection by human viruses and has become a preferred model for a number of human respiratory pathogens including respiratory syncytial virus (RSV), influenza (A and B), adenoviruses (several serotypes), parainfluenza virus (type 3), and measles. The long term goal of this project is to use the cotton rat to establish a reliable model of HRV infection. Based on the well-documented susceptibility of the cotton rat to a diversity of human viruses and our own preliminary studies indicating that intranasal infection with HRV16 results in respiratory tract pathology in the cotton rat we proposed to First, Delineate the characteristics of acute HRV16 infection in cotton rats by (a) defining the kinetics of HRV16 infection; (b) selecting clinical parameters that can be use to follow acute disease; (c) describing the HRV16-induced pathology of the upper and lower respiratory tract; and (d) defining the expression of cytokines and chemokines resulting from HRV-16 infection. Secondly, we will focus in the characterization of the protective immunological response generated by HRV16 infection in the cotton rats. A strong team of investigators has been assembled combining extensive expertise in the use of cotton rats and strong virology capabilities. If successful, the proposed research will result in a valuable experimental resource to test vaccines and therapeutics against the "common cold".