Development of the Cotton Rat Model of Rhinovirus Infection and Disease

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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