This application is focused on the paradoxical role of innate immune and antiviral responses in the dysregulation of critical cytoprotective responses in the lung. We have previously discovered that an unbalanced reactive oxygen species (ROS) production in the course of respiratory syncytial virus (RSV) infection, the major cause of lower respiratory tract infections (LRTI) in infants, is caused by a progressive reduction in nuclear and cellular levels of the transcription factor NF-E2-related factor 2 (NRF2), the primary regulator of antioxidant enzyme (AOE) gene expression. This process, which contributes to lung disease and inflammation, occurs through deacetylation and increased degradation of NRF2 via the proteasome pathway and leads to decreased expression of AOEs in RSV-infected airway epithelial cells (AECs), in experimental mice, as well as, in children with naturally acquired RSV LRTI. RSV-mediated NRF2 degradation occurs via the sumoylation-dependent ubiquitin ligase RNF4, which is recruited to the promyelocytic leukemia protein nuclear bodies (PML-NBs) in conditions of cellular oxidative stress. In the absence of IFN-dependent signaling, we found no induction of PML protein, a major component of PML-NBs, in response to RSV infection and significantly reduced NRF2 degradation, resulting in enhanced AOE gene expression. Moreover, mice lacking type I IFN receptor (IFNR1 -/-) display significant reduction of lung inflammation and overall improvement in clinical disease. RSV infection in infants and young children is known to be poorly responsive to the canonical antiviral activity of interferons (IFNs), whereas evidence of overexpression of IFN genes in lung and blood has been shown to be associated with immune dysregulation. In addition, preliminary studies indicated that lack of NF-?B activation revert RSV-induced decrease in NRF2 acetylation, restoring its cellular and nuclear levels, with subsequent increase in NRF2-dependent gene transcription and AOE gene expression. Based on these data, we will test the hypothesis that RSV-induced proinflammatory and antiviral pathways play a central role in the RSV-induced demise of NRF2, leading to lung oxidative injury and ROS-dependent disease pathogenesis. These studies will provide initial experimental evidence that modulation of the IFN pathway could represent a possible target for therapeutic intervention for RSV-induced oxidative lung damage and inflammation. .
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