Mechanisms of Respiratory Syncytial Virus-Induced Mucus" Viral Strain Dependence

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DESCRIPTION (provided by applicant): My Ph.D. training is in viral pathogenesis and mouse models of viral disease. The major theme of my research is utilizing mouse models and viral genetics to study viral pathogenesis in vivo. In my postdoctoral fellowship, I am investigating respiratory syncytial virus (RSV) pathogenesis in the laboratory of Stokes Peebles, MD at Vanderbilt. My education, training, and productivity are enhanced by a mentor with strong basic science and clinical backgrounds as well as the departmental and institutional environments. My immediate goals are to progress with the Aims of this proposal and obtain an assistant professor position at a biomedical research institution. We reported that infection of mice with the RSV line 19 strain, but not the A2 strain resulted in mucus production, lung IL 13 expression, and airway dysfunction. Thus, the line 19 strain of RSV is a model for investigating RSV-induced mucus/airway dysfunction. We sequenced the line 19 genome and identified RSV mucus-inducing gene candidates. Aim 1 will utilize RSV reverse genetics to map the region of the line 19 genome sufficient for infection-induced mucus/airway dysfunction. We found that distinct clinical isolate RSV strains induce differential pathogenesis in mice. RSV A/2001/2 20 strain induces higher lung IL 13 and airway mucus expression, as well as greater disease severity and histopathology in mice than the A2, line 19, and A/2001/3 12 strains. Aim 2 will utilize RSV reverse genetics to map the gene(s) of A/2001/2-20 sufficient for elevated pathogenicity compared to the A/2001/3 12, a co-circulating RSV strain. Aim 2 will also define the roles of IL 13 and STAT6 in A/2001/2-20 pathogenesis. Defining mechanisms and the molecular basis of RSV strain-specific pathogenesis will improve our understanding of the sequelae of RSV. My long-term objectives are to be a productive, independent investigator in the field of viral pathogenesis and provide insights into RSV pathogenesis that translate into therapies and/or vaccines for RSV disease. My research will emphasize viral immunology and mechanisms of pulmonary pathogenesis. My long-term research goals are to elucidate mechanisms by which RSV causes mucus production/airway dysfunction and define how RSV genotype diversity affects RSV immunopathogenesis. The Future Directions section describes how the Specific Aims here will lead to hypotheses towards my long-term goals. Relevance: RSV causes >100,000 infant hospitalizations in the US each year and is the leading cause of bronchiolitis and viral pneumonia in infants. Mucus production is a hallmark feature of RSV disease, leading to airway obstruction, hypoxia, and mechanical ventilation. Mechanisms of RSV-induced mucus are unknown and the focus of this proposal. Elucidation of these mechanisms will identify targets for therapies.