Center in Environmental Toxicology

The natural history of asthma begins early in life when infants are exposed to respiratory infections, in particular those caused by respiratory syncytial virus (RSV). Indeed, RSV is the single most important virus causing acute respiratory-tract infections (bronchiolitis) in the first year of life. In addition to acute morbidity, severe RSV infections in infants, those that require hospitalization, have been linked to both the development and the severity of asthma. Vaccines or specific therapies are not currently available for RSV infections.

Over the past 15 years our research program has focused on the pathogenesis of RSV infection and its relationship to asthma, using cellular models, experimental rodent infection and clinical investigations in patients with naturally-acquired infections. As members of the NIEHS theme "Asthma pathogenesis", the PI of this pilot application has initiated studies addressing the effect of environmental exposure to second hand tobacco smoke (SHTS) on severity of RSV-induced bronchiolitis. Indeed, exposure to SHTS may occur in up to 60% of the infants with RSV bronchiolitis in the US, and different studies have suggested that ETS is a risk factor for the development of severe infections.

In a series of studies in vitro and in vivo, we have discovered that in the course of RSV infections reactive oxygen species (ROS) are rapidly generated and cause lung inflammation and clinical disease. Specifically, we have demonstrated that ROS are involved in the signaling transduction pathways that control inducible expression of chemokine and other inflammatory genes in response to RSV infection, yet blocking ROS production does not significantly increase viral replication in the lung and even decreases viral replication in cells. Recently, in the course of proteomics studies aimed to profile global protein expression Drs. Hosakote and Casola made two important discoveries never reported before: 1) RSV potently inhibits the expression of antioxidant enzyme (AOE) genes, including Glutathione S-transferases (GSTs), Superoxide dismutases (SOD) and catalase; 2) following RSV infection, expression of nuclear NF-E2 related factor-3 (Nrf3), which negatively regulates AOE gene expression, is induced in epithelial cells, while Nrf2, which positively regulates basal and inducible expression of AOE genes is downregulated both in cells and in the lung. We have also shown that oxidative-driven inflammatory events in RSV-infected epithelial cells are exacerbated by exposure of cells to tobacco products. Our hypothesis is that the viral-mediated inhibition of cytoprotective AOE and exposure to SHTS leads to severe manifestations of RSV infections, which are major risk factors for the development of asthma precipitation of acute wheezing. We will (start to) address our general hypothesis by the following Aims: 1) To determine the mechanism(s) of inhibition of AOE expression in the lung during the course of RSV infection by investigating the role of Nrf-mediated transcription pathways; 2) To establish whether pharmacologic intervention aimed to increase Nrf2 activation in the airways or to supplement the antioxidant response via synthetic antioxidant mimetics results in protection from viral-induced lung injury and clinical disease; 3) Analyze whether distinct AOE expression patterns at the airway mucosal site can discriminate between infants with different severity of illness and/or exposure to SHTS in naturally-acquired RSV infections.

Work proposed in this pilot application will be critical for the competitiveness of three grant applications, which are going to be submitted, including 1) Thrasher Research Fund Clinical Translational Grant in Pediatric Research by the title "NRF2 controls oxidative responses in viral bronchiolitis" (new); 2) NIH R01 – "Genetics and environmental determinants of viral bronchiolitis (new)"; 3) NIH P01 – "Signaling in Airway Inflammation" (competitive renewal).