PROJECT 3: Respiratory syncytial virus (RSV) is the leading cause of respiratory failure in young children and severe RSV bronchiolitis has been identified as risk factor for the subsequent development of asthma in children. Currently, there is no effective vaccine for RSV and pharmacologic treatment is far from optimal. Development of new therapeutic agents is critical to reduce the morbidity and mortality from this important pathogen, and to perhaps modify the risk of childhood asthma. Our preliminary data suggest that prostaglandin (PG) 12 is a novel therapeutic target for RSV. In a well characterized murine model of RSV infection, we reported that transgenic mice that constitutively overexpress PGI synthase (PGIS) were significantly protected from RSV-induced illness. In addition, we found that mice which cannot signal through the PGI2 receptor (IP) had significantly exacerbated weight loss and delayed recovery after RSV infection. Further, in a collaborative study of infants admitted with RSV bronchiolitis, we found that a functional polymorphism in the promoter region of the PGI synthase (PGIS) gene was associated with an increase in the urinary PGI2 metabolite and less severe bronchiolitis. These data strongly suggest that PGI2 and IP signaling protect against RSV-induced disease. The long term objective of this application are to define role of PGI2 in RSV-induced airway pathophysiology and the mechanism by which PGI2 protects against RSV-induced illness. We have isolated an RSV strain (01/2-20) from an infant with bronchiolitis that induced airway responsiveness, airway mucus expression, and high levels of lung IL-13 protein in mice.
In aim 1, we hypothesize that PGI2 and IP signaling protects against RSV 01/2-20 -induced airway responsiveness, inflammation, and pathology. We also have preliminary data which reveals that PGI2 selectively downregulates bone marrow derived dendritic cell and macrophage expression of TLR4, a pattern recognition receptor that is activated by the RSV F protein.
In aim 2 we hypothesize that PGI2 modulates RSV-induced immunopathology in a TLR4-dependent manner. The proposed studies may result in a novel, effective therapy for RSV bronchiolitis.
RSV is the leading cause of bronchiolitis and causes >100,000 infant hopsitalizations 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 role of PGI2 in RSV-induced airway disease.
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