Modeling severe respiratory syncytial virus pathogenesis in bronchopulmonarydysplasia

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Project Summary/Abstract Currently, the molecular and cellular mechanisms underlying the enhanced disease development of RSV infection in children with bronchopulmonary dysplasia (BPD) is elusive, largely due to the lack of animal studies to model severe RSV infection in this at-risk group of patients. We have recently established a clinically- relevant neonatal hyperoxia model of prematurity and BPD in the lab. In this application, we wish to use this model to examine the mechanisms of severe disease development following RSV infection in BPD hosts. Two specific aims are proposed: Aim1: To test the hypothesis that neonatal hyperoxia predisposes the hosts to severe RSV-associated diseases. Aim 2: To test the hypothesis that exaggerated Gadd45b expression promotes acute RSV-associated diseases in BPD hosts. Relevance statement Respiratory syncytial virus (RSV) is the most frequent cause of serious lower respiratory-tract illness in infants. Severe RSV infection is prominent in preterm infants and particularly dangerous in children with BPD, a chronic lung disease of infants born extremely premature and characterized by abnormal development of structure and function. Of note, the incidence of BPD is increasing globally due to the improved survival rate of extremely premature infants. Following initial hospital discharge of preterm or BPD infants, viral respiratory infections, most commonly with RSV, result in increased hospitalization, healthcare utilization, and increased respiratory morbidity. These clinical data suggest that preterm patients, particularly BPD patients, are highly susceptible to RSV infection and develop severe pulmonary diseases following RSV infection. The knowledge generated from this study will significantly improve our understanding on RSV pathogenicity in BPD hosts. Furthermore, we expect that this application will promise to open the door for novel therapeutic strategies aiming to minimize viral pathogenesis and chronic lung conditions in BPD patients (for instance, targeting on Gadd45b pathway).