Development of the Cotton Rat Model of Rhinovirus Infection and Disease

描述(申请人提供)：人类鼻病毒(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疾病(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。尽管这个问题很重要，但目前还没有有效预防HRV感染或治疗HRV相关疾病的方法。在从老鼠到猴子的许多物种中建立HRV感染的小动物模型的尝试都失败了，从而严重阻碍了针对HRV感染的机制研究和疫苗和疗法的开发。与实验室的小鼠和大鼠不同，棉鼠对人类病毒的感染表现出独特的敏感性，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(A和B)、腺病毒(几种血清型)、副流感病毒(3型)和麻疹。该项目的长期目标是利用棉鼠建立可靠的HRV感染模型。基于大量文献证明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HRV16会导致棉花鼠的呼吸道病理，我们建议首先描述棉花鼠急性HRV16感染的特征，方法是：(A)定义HRV16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HRV16诱导的上呼吸道和下呼吸道的病理；以及(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，我们将重点研究HRV16感染棉花大鼠所产生的保护性免疫反应。已经组建了一支强大的调查团队，结合了使用棉鼠的广泛专业知识和强大的病毒学能力。如果成功，拟议的研究将导致 测试针对“普通感冒”的疫苗和疗法的宝贵实验资源。 与公共卫生相关：人类鼻病毒是最常见的感冒和流感样疾病的原因。此外，鼻病毒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疾病。在许多动物中建立鼻病毒感染的小动物模型的尝试都失败了，从而严重阻碍了机制研究以及针对HRV感染的疫苗和治疗药物的开发。该项目的目的是首次利用棉花大鼠建立鼻病毒感染模型

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". PUBLIC HEALTH RELEVANCE: Human rhinoviruses are the cause of most common colds and flu-like illnesses. In addition rhinovirus infections are associated with disease of considerable severity, such as exacerbation of asthma, wheezing illness in children, and chronic obstructive pulmonary disease. Attempts to develop a small animal model of rhinovirus infection in many animal species have failed, thus severely hampering mechanistic studies and the development of vaccines and therapeutics against HRV infection. The purpose of this project is to generate for the first time a model of rhinovirus infection using the cotton rat