Why Are Steroids Ineffective at Suppressing RSV Bronchiolitis

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DESCRIPTION (provided by applicant): We have recently discovered expression of the Non-Structural protein 2 of Respiratory Syncytial Virus (RSV) is responsible for hallmark characteristics of RSV infection of human airway epithelium. Using recombinant Parainfluenza Virus (PIV) expressing RSV NS2 and relevant models of human and hamster columnar airway epithelium we show RSV NS2 has a dramatic effect on the fate of PIV-infected cells resulting in a striking shedding of virus-infected epithelial cells into the airway lumen and a hyper-inflammatory phenotype. In hamster distal airways, shedding cells accumulate in the narrow lumens causing acute distal airway obstruction accompanied by exaggerated recruitment of inflammatory cells. These histologic findings are remarkably similar to those found in airways of human infants with RSV bronchiolitis and suggest PIV- mediated RSV NS2 expression in hamster bronchioles represent a novel animal model for investigating early initiating events of bronchiolitis. We are eager to use this model to test therapeutic approaches for reducing the severity of RSV bronchiolitis and envision strategies that lessen the consequences of RSV NS2 expression may provide therapeutic benefit to infants with RSV bronchiolitis. Our first use of this model will be to explore a significant clinical question; why steroids fail to suppress RSV-induced inflammation while effectively suppressing inflammation induced by PIV? Using relevant models of columnar airway epithelium we test whether RSV NS2 expression renders PIV-induced inflammation resistant to steroids in vitro and in vivo. We also test the efficacy of a novel class of non-steroidal anti- inflammatory modulators, the synthetic triterpenoids, to suppress consequences of RSV NS2 expression as these drugs have shown great promise as anti-inflammatory agents but without the adverse effects of steroids and are currently in human clinical trials for non-respiratory indications. Our notion is RSV NS2-induced inflammation, while resistant to steroids, may be suppressed by triterpenoids. Finally, to capitalize on the wealth of mouse genetic models and related reagents we engineer mouse respiratory viruses to express RSV NS2 and test whether infection of mouse airways with these novel chimeric viruses results in distal airway obstruction and exaggerated airway inflammation; thus, providing a useful animal model for future mechanistic studies. RSV bronchiolitis is the single largest cause of hospitalization of infants. Here, we develop animal models in which RSV NS2 expression in distal airways recapitulates hallmark characteristics of RSV bronchiolitis in infants. These studies will provide a novel platform for developing and testing therapeutics for relieving the onset and severity of RSV bronchiolitis in humans.