The long term objective of this application is to define the relationship between infant respiratory syncytial virus (RSV) infection and the host response that enables asthma inception. There is abundant evidence that children who experience severe RSV bronchiolitis during infancy are at greater risk for developing asthma later in childhood;however the host and viral determinants of severity of illness are not fully defined. Also unknown is whether mild RSV-induced illness in infancy may protect against the subsequent development of childhood asthma. In Project 1, we utilize the ReSPIRA (Respiratory Study for Protection of Infants from RSV to Asthma) cohort of 2000 infants to focus on host immune responses to RSV infection and the subsequent risk of recurrent wheezing and childhood asthma. Specifically, in Project 1 we will a) establish the relationship between the host phenotypic response to RSV infection in the first 6 months of life and the risk of recurrent wheeze and asthma, and b) identify the host genetic and immune response determinants of the RSV infection phenotype that affect the development of early childhood wheezing and asthma following RSV infection. In Project 2, we will focus on the contribution of specific RSV strains to early childhood wheezing and asthma development. RSV strains isolated from the ReSPIRA cohort will be genotyped and clinical parameters such as bronchiolitis severity score, as well as mediators of the host immune response measured in respiratory secretions will be studied to determine how RSV genotypes impact the host response. In Project 3, we will utilize a mouse model of RSV infection to examine the role of the prostaglandin 12 (PGI2) on airway dysfunction of an RSV strain (01/2-20) that has been associated with severe infant bronchiolitis and which induces airway pathology in the mouse. We previously reported that PG12 and signaling through its receptor (IP) is a critical determinant of severity of illness in RSV strain A2 infection. This project will determine the role of host PGI2 in RSV airway pathogenesis and also determine if a PGI2 analog currently used in the treatment of human disease is a target for RSV bronchiolitis. Further, in Project 3, we will use RSV strains isolated from ReSPIRA in Project 2 to determine the generalizability of PGI2 as a therapeutic target.
PUBLIC HEATH RELEVANCE (provided by applicant): RSV is the leading cause of bronchiolitis and causes >100,000 infant hospitalizations in the US each year. Studies have also revealed that severe RSV infection in infancy is associated with the later development of childhood asthma. This application will examine the effects of both host genetic and immune response determinants, as well as the influence of specific RSV strains, on severity of RSV bronchiolitis and childhood asthma. In addition, we will define the role of a novel therapeutic target, PG12, in RSV pathogenesis.
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