Mechanisms and Enviromental Determinants of Rhinovirus Illness Severity

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DESCRIPTION (as provided by applicant): Recent studies utilizing PCR-based diagnostics have demonstrated that rhinovirus (HRV) is an important cause of lower respiratory illness including bronchiolitis, influenza-like illness, and exacerbations of chronic lung diseases such as asthma, cystic fibrosis, and chronic obstructive lung disease (COPD). In addition, HRV wheezing illnesses in the first three years of life are among the strongest risk factors for subsequent asthma. The lack of specific treatments and preventive strategies for more severe HRV illnesses and exacerbations of asthma is a major unmet medical need. To address this therapeutic gap, we propose a novel program of three interrelated projects to identify risk factors and pathogenic mechanisms related to the virus, host immune response, and environment that determine the severity of HRV illnesses. The clinical centerpiece of the program is the proposed Wisconsin Infant Immune & Illness Surveillance Cohort ("WISC", Project 1), which will define how a naturally-occurring intervention, farm exposure in early childhood, enhances immune maturation and antiviral responses, and reduces morbidity from viral respiratory illnesses. Defining distinct farm-related patterns of immune maturation that mediate protection from viral illnesses will provide a road map for new preventive approaches intended to minimize respiratory morbidity for children growing up in other environments. In Project 2, Dr. Ann Palmenberg and colleagues propose to use novel tissue culture systems and molecular approaches to define the pathogenesis of the newly described HRV-C species, focusing on identification of the cellular receptor and clinical consequences of unique 2Apro structure and biochemistry. Finally, in Project 3, Dr. John Yin will use novel techniques (fluorescent-tagged HRVs and indicator cell lines, real-time fluorescent microscopy) to reveal how HRV replication in single cells stimulates immune responses and define mechanisms of spread to neighboring cells. Collectively, these three projects will extensively share clinical samples, expertise and conceptual advances to identify new targets for the treatment and prevention of HRV infections. RELEVANCE: Rhinoviruses, originally known as "common cold viruses", also cause lower respiratory illnesses such as childhood wheezing, influenza-like illness, and exacerbations of asthma and COPD. Unfortunately, no treatments or vaccines are available for HRV infections. We propose to identify new environmental and molecular determinants of HRV illness severity that will serve as a basis for new treatment strategies. Project 1: Impact of Farming Environment on Immune Maturation and Respiratory Health Project Leader (PL): Gern, James DESCRIPTION (as provided by applicant): The major goal of this proposal is to better understand immune maturation and its relationship to viral respiratory infection disease severity. Viral respiratory infections (VRI) are a significant health risk to infants. These common childhood infections, for which few therapeutics or effective vaccines exist, result in significant morbidity and mortality during the first five years of life. As such, VRIs are a significant public health problem impacting the quality of life of affected children and places increased societal strain in the workplace and on health care utilization. Additionally VRIs appear to have a long lasting health impact, for example in some children resulting in the development of chronic allergic diseases. Uniquely, unpublished data from MESA demonstrate significantly decreased respiratory infections during the first two years of life in farm children compared to non-farm children. These effects parallel published findings from around the world that farm exposures lower the risk of childhood allergies and asthma. Notably, the development of allergen sensitization and highest vulnerability to VRIs coincides with the maturation phase of the immune system, and there is evidence that farm exposures enhance development of innate immunity and T regulatory (Treg) cell function. We hypothesize that farm exposures reduce the risk of VRIs in young children by enhancing the development of innate antiviral immunity and Treg function. To test this hypothesis, we will develop a unique birth cohort study from Wisconsin farm and non-farm families within MESA. Functional assays to define innate and Treg cell maturation will be utilized in a longitudinal manner along with surveillance of VRIs and allergic sensitization. A better mechanistic understanding of how environmental exposures promote resistance to VRIs and diminish allergic diseases through effects on immune maturation will allow for development of new strategies to bring benefits of farm exposures to those who live elsewhere. In addition to addressing these research goals, this project will serve as a source of extensively characterized clinical specimens (airway epithelial cells, clinical isolates of rhinoviruses) that will enable mechanistic studies to define host-virus interactions tht contribute to the severity of clinical illnesses. RELEVANCE: Viral respiratory infections (VRI) are ubiquitous, cause significant morbidity and mortality in early life, and effective vaccines or therapies are lacking. Farm exposures in early life appear to promote immune maturation, and we have new data to show that farm children have significantly fewer respiratory illnesses. In this proposal, we will assemble a novel birth cohort to better farm effects on immune maturation and viral respiratory illnesses. The goal of this study is to identify new targets for the treatment and prevention of VRI.