Mechanisms of particulate matter driven infant respiratory disease

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Project Summary Intrauterine exposure to ambient particulate matter (PM) air pollution has been associated with increased lower respiratory tract infections (LRTIs) in infants. Despite the known sensitivity of the fetus to environmental pollutants and epidemiological evidence correlating prenatal PM exposure and LRTI morbidity, mechanisms of PM enhanced pathogenesis are relatively unexplored in immunologically immature populations. Preliminary data from our novel intrauterine murine exposure model demonstrate the reduced ability of immature offspring exposed to PM in utero to develop a robust inflammatory response. Based on these data and similar results in our neonatal (i.e., <7 days of age) exposure model indicating increased respiratory infection severity following early life exposure to air pollution, we hypothesized this window of immunosuppression correlates with offspring susceptibility to severe respiratory syncytial virus (RSV) disease. RSV infection represents a significant cause infant respiratory morbidity and mortality. Its pathogenesis is known to be impacted by similar pathways affected by PM-induced oxidative stress, namely the nuclear factor erythroid 2-related transcription factor (Nrf2) antioxidant response pathway. Polymorphisms impacting maternal Nrf2 signaling have recently been reported to increase LRTI risk in infants exposed to PM in utero. Thus, to test our hypothesis and clarify the impact of maternal ability to respond to oxidative stress on offspring RSV disease severity, we will carry out two specific aims in the proposed project. In Aim 1, we will combine our novel intrauterine exposure model with our 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 immune responses. In Aim 2, we will use Nrf2-deficient and wild-type mice to investigate the role of maternal Nrf2 expression on offspring pulmonary oxidative stress responses to intrauterine PM and RSV susceptibility. We will further probe the protective role of Nrf2 through maternal dietary supplementation with a known Nrf2 inducer. Outcomes from this research will provide important insight to understand interactions between genetic and environmental determinants of immunopathogenesis of RSV infection. These findings will aid in identifying susceptible subgroups of children and establish the proof-of-principle for targeting the Nrf2 response pathway in mothers exposed to air pollution for the protection against childhood respiratory disease, a pervasive public health problem affecting millions of children worldwide.