PROJECT 2: Our long-term goal is to elucidate mechanisms by which respiratory syncytial virus (RSV) contributes to asthma pathogenesis. RSV is the leading cause of infant bronchiolitis and a major cause of asthma attacks. RSV is likely involved in asthma development. Severe RSV bronchiolitis in infancy is associated with childhood asthma. Our data suggest that different RSV strains cause differential acute disease severity, both in infants and in experimentally infected mice. Our central hypothesis is that more virulent RSV strains will be tightly associated with early childhood wheezing and asthma development and cause greater epithelial damage, TH2-type inflammation, and airway mucus expression. Our project represents a synergy between RSV molecular epidemiology and mechanistic mouse models of RSV pathogenesis. It is part of a larger study focusing on mechanisms of bronchiolitis-to-asthma in children. The ReSPIRA (Respiratory Study Protection Infection RSV Asthma) cohort will follow 2000 infants until 3-4 years of age. We expect 20-30% of infants will have RSV lower respiratory tract infection (severe), 35-40% will have mild RSV infection, and 35-40% will have no RSV infection detectable. Clinical characteristics of illness will be defined, including a quantitative bronchiolitis severity score (BSS) and prolonged wheezing. We will genotype the approximately 1000 anticipated RSV isolates from the ReSPIRA cohort. We will construct dendrograms to define genetic relatedness of the RSV strains. In collaboration with Dr. Tina Hartert's group (Vanderbilt), we will analyze RSV genotypes and clinical parameters such as BSS and prolonged wheezing to define the role of RSV strain differences in disease seventy and asthma development. We will measure cytokine/chemokine levels in patient respiratory secretions to define how RSV genotypes impact the host response. We will investigate mechanisms of ReSPIRA RSV strain pathogenesis in a mouse model. We hypothesize that different ReSPIRA RSVs will cause differential lung IL 13 and mucus expression and epithelial damage in mice. We will investigate the role of neutrophils in ReSPIRA RSV infection by neutrophil depletion. We will define the role of RSV fusion protein variability in differential pathogenesis using a RSV reverse genetics strategy.
RSV causes >100,000 infant hospitalizations in the US each year and is the leading cause of bronchiolitis and viral death in infants. Mucus production is a hallmark feature of RSV disease. Identification of differentially virulent, mucogenic, and/or asthmagenic RSV strains may lead to targeted vaccines for RSV that reduce the clinical burden of RSV and RSV-potentiated asthma.
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