Susceptibility to viral infection driving lung injury and disruption of lung development in neonates with bronchopulmonary dysplasia
Bronchopulmonary dysplasia (BPD) is a common and serious complication of preterm birth that is associated with a pronounced stunting of the post-natal growth and impaired development of the immature lung. Patients with BPD exhibit an increased risk for respiratory syncytial virus (RSV) and influenza virus (IV) infection. Furthermore, the presence of RSV or IV as comorbidities with BPD results in increased disease severity and a worse clinical outcome, however, no study to date has explored the interactions between BPD and virus infection.
Our previous work revealed that murine BPD is associated with substantial alterations of the inflammatory cell phenotype within the developing lung, and the impaired alveolar development correlated with recruitment of defined inflammatory cell subsets, suggesting that viral infection-associated inflammatory responses may indeed cross-talk with developmental pathways in the BDP lung to promote the disease phenotype, and vice versa, BPD lungs may be particularly permissive for viral infection due to disturbed host defense mechanisms. Using an established mouse model of BPD, we will address the following questions:
(i) Does pre-existing BPD predispose affected lungs to increased susceptibility to RSV or IV infection, leading to more severe lung injury and more pronounced respiratory failure?
(ii) Does RSV or IV infection in the background of BPD exacerbate the blunted lung development that is associated with BPD?
(iii) What mechanisms underlie the physiological interactions between virus infection and BPD?
To address these mechanisms, we will establish whether the presence of BPD creates an immunologically permissive environment for RSV and IV infection, and whether the presence of BPD modulates either the viral processing systems of the host lung, or important regulatory growth factor networks required for virus persistence. Once candidate mediators of the interaction between BPD and virus infection have been identified, we envision to draw clinical correlations in terms of mediators of BPD and virus interaction in the blood or endotracheal aspirates of infants, and also, radiological evidence of perturbations to lung development, in a cohort of preterm infants with and without BPD and confirmed viral infection.
The outcome of the proposed research will fill a key gap in our medical knowledge, furthering our understanding of how BPD influences the course of RSV and IV infection, and vice versa. These findings have the potential to substantially improve the medical management of the very high-risk group of BPD patients.