Project Details
Projekt
Susceptibility to viral infection driving lung injury and disruption of lung development in neonates with bronchopulmonary dysplasia
Applicants
Professorin Dr. Eva Böttcher-Friebertshäuser; Professor Dr. Harald Ehrhardt; Professor Dr. Rory Edward Morty, Ph.D.
Subject Area
Clinical Infectiology and Tropical Medicine
Term
from 2016 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 284237345
Bronchopulmonary dysplasia (BPD) is the most common and severe complication of preterm birth, characterized by stunted lung development due to oxygen support in the neonatal period, with medically relevant consequences for respiratory health lasting into adulthood. Affected infants receiving oxygen supplementation are at risk for increased susceptibility to respiratory virus infection, namely influenza virus (IV) and respiratory syncytial virus (RSV). Furthermore, the severity of BPD is worsened when affected infants develop respiratory virus infections, either in the neonatal period; or after discharge. Despite the medically important link between preterm birth, oxygen support, and respiratory virus infections, no study to date has examined the mechanisms by which oxygen support can increase the permissiveness of the lung for viral infection, or whether the combination of lung immaturity, oxygen support, and respiratory virus infection worsens lung development in affected infants. Data generated during the first funding period of this study revealed that oxygen support increases the permissiveness of the lung for viral infections, when RSV infection was modelled in newborn muse pups using pneumonia virus of mice (PVM). Similarly, the combination of oxygen toxicity and PVM infection in the developing lung led to worsening of lung development, compared with oxygen-injured lungs alone. In oxygen-injured lungs, resident alveolar macrophages were identified to be pivotal pathogenic mediators of arrested lung development, and oxygen injury to the developing lung was documented to increase host protease activity, which may have facilitated viral replication and infection, which is thus predicted to increase viral susceptibility in developing lungs. In the second funding period, it is intended to explore the interaction between lung immaturity, viral infection, and oxygen support, at a mechanistic level; to facilitate our understanding of how a hyperoxic and viral insults act cooperatively to drive worsening disease. Amongst the aims are to (i) identify the resident alveolar macrophage subpopulations that mediates the impact of hyperoxia on lung development; (ii) identify the mechanisms by which oxygen toxicity drives the phenotypical transformation of lung inflammatory cells to promote viral infection, and to stunt lung development; (iii) identify which host proteases are modulated by oxygen toxicity which then creates a permissive environment for viral infection, and thus, increases the susceptibility of the oxygen-injured developing mouse lung to PVM infection; and (iv) interrogate pharyngeal fluid harvested from BPD patients with and without respiratory virus infection, to assess whether clinical correlations may be drawn with the preclinical model, with the aim of improving medical management of affected infants to improve resistance to viral infection, and promote proper lung development, in the background of oxygen support.
DFG Programme
Clinical Research Units
