Epidemiological data support a causal link between exposure to elevated levels of particulate matter (PM) and increased lower respiratory tract infections (LRTIs) in children. During the H1N1 influenza (Flu) pandemic, exposure to PM was a potential contributing factor to the disparity in the increased levels of H1N1-induced morbidity and mortality observed in Mexico and the United States. Interestingly, the risk of LRTIs due to PM exposure is highest in infants. Despite strong evidence associating PM exposure and LRTI susceptibility, morbidity, and mortality in infants; there is very little research on this subject nd the mechanisms underlying this phenomenon are unknown. We have developed a novel neonatal (<7d of age) rodent model for studying PM exposures, which we apply here to understand the effects of PM on enhanced susceptibility to LRTI and LRTI-mediated disease severity. We show that age of exposure to PM is important in predicting LRTI disease sequela and that infant exposure to PM initiated several events that may explain the epidemiological data. First, exposure of neonatal mice to PM results in epithelial disruption. Second, adaptive immune responses following PM exposure in neonates are suppressive in nature (i.e. increased IL10 and Treg cells and decreased Th1, Tc1, and Th17 cell numbers) and not protective. The end result is enhanced severity of Flumediated disease as evidenced by increased pulmonary viral loads and mortality in neonatal mice infected following exposure to PM. Our data further suggest that PM-induced epithelial signals either cell associated or secreted (i.e. epimmunome) are used to direct this aberrant immune response to Flu by programming dendritic cells (DCs). Thus, we hypothesize that exposure to PM during infancy increases the severity of infectious respiratory disease through a process involving alteration of the epimmunome.
Aim 1 will test the hypothesis that neonatal exposure to PM suppresses pulmonary host defense against Flu and enhances disease.
Aim 2 will define downstream regulatory T cell mechanisms induced by PM exposure which suppress the immune response to Flu. Our preliminary data indicate a role for IL10 and regulatory T cells in enhanced Flu-mediated disease. We will first determine the source of PM-induced IL10 using reporter mice and examine the necessity for IL10 in PM exposure enhanced Flu severity using IL10 deficient mice and IL10 reconstitution experiments.
Aim 3 will determine the upstream signals from PM altered airway epithelium that dictate dendritic cell (DC) phenotype which in turn influences T cell responses. These studies will be accomplished using DC specific ?-catenin knockout mice and our recently developed neonatal epithelial:DC co-culture system to explore the role of ?-catenin signaling in DC function. Completion of these studies will provide us with an understanding of the molecular signaling events between injured epithelial cells and DCs crucial to understand how PM exposure alters Flu pathogenesis in infants and to identify pharmacologic targets for the treatment of environmentally-induced asthma exacerbations due to LRTI.
Elevated levels of PM increase risk of infant mortality from lower respiratory tract infections such as influenza; and yet, few studies have tried to understand the mechanisms responsible for increased risk for LRTIs in this population following exposure to PM. Despite these facts, there is an urgent need for research in this area to understand the public health risks and develop therapeutic interventions. The concepts established here will have important implications for understanding mechanisms of PM-mediated airway disease and for understanding mechanisms of the epimmunome relevant to reducing morbidity and mortality associated with PM-exacerbated LRTI.
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