Mechanisms of Particulate Matter Driven Infant Respiratory Disease
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Project SummaryIntrauterine exposure to ambient particulate matter (PM) air pollution has been associated with increased lowerrespiratory tract infections (LRTIs) in infants. Despite the known sensitivity of the fetus to environmentalpollutants and epidemiological evidence correlating prenatal PM exposure and LRTI morbidity, mechanisms ofPM enhanced pathogenesis are relatively unexplored in immunologically immature populations. Preliminarydata from our novel intrauterine murine exposure model demonstrate the reduced ability of immature offspringexposed to PM in utero to develop a robust inflammatory response. Based on these data and similar results inour neonatal (i.e., <7 days of age) exposure model indicating increased respiratory infection severity followingearly life exposure to air pollution, we hypothesized this window of immunosuppression correlates withoffspring susceptibility to severe respiratory syncytial virus (RSV) disease. RSV infection represents asignificant cause infant respiratory morbidity and mortality. Its pathogenesis is known to be impacted by similarpathways affected by PM-induced oxidative stress, namely the nuclear factor erythroid 2-related transcriptionfactor (Nrf2) antioxidant response pathway. Polymorphisms impacting maternal Nrf2 signaling have recentlybeen reported to increase LRTI risk in infants exposed to PM in utero. Thus, to test our hypothesis and clarifythe impact of maternal ability to respond to oxidative stress on offspring RSV disease severity, we will carry outtwo specific aims in the proposed project. In Aim 1, we will combine our novel intrauterine exposure model withour well-characterized neonatal mouse model of RSV infection to characterize RSV infection severity.Specifically, we will determine how altered pulmonary T cell profiles influence offspring adaptive immuneresponses. In Aim 2, we will use Nrf2-deficient and wild-type mice to investigate the role of maternal Nrf2expression on offspring pulmonary oxidative stress responses to intrauterine PM and RSV susceptibility. Wewill further probe the protective role of Nrf2 through maternal dietary supplementation with a known Nrf2inducer. Outcomes from this research will provide important insight to understand interactions between geneticand environmental determinants of immunopathogenesis of RSV infection. These findings will aid in identifyingsusceptible subgroups of children and establish the proof-of-principle for targeting the Nrf2 response pathwayin mothers exposed to air pollution for the protection against childhood respiratory disease, a pervasive publichealth problem affecting millions of children worldwide.
