Sunday, March 23, 2025
3/23/2025
PROJECT SUMMARY/ABSTRACT: Epidemiological data support a causal link between exposure to elevated levels of particulate matter (PM) and increased lower respiratory tract infections (LRTIs), such as influenza (Flu), in children. Despite strong evidence associating PM exposure and LRTI susceptibility, morbidity, and mortality in infants; there is sparse research on the mechanisms underlying this phenomenon and therefore the delineation of these mechanisms is our long-term goal. In the past grant cycle, we showed that PM exposure damages the airway epithelium in a novel neonatal mouse model, leading to 1) impaired epithelial barrier function; and 2) suppressive pulmonary immune responses mediated via regulatory T cells that are collectively responsible for PM-enhanced Flu morbidity. IL22 is essential in regulating pulmonary epithelial repair responses and in the resolution of lung inflammation during Flu infection. Our data demonstrate a role for IL22 in PM-enhanced Flu severity. Aryl hydrocarbon receptor (AhR) has been shown to be a major regulator for IL22 expression. It is noteworthy that PM exposure induced transient activation of the AhR similar to IL22 responses in the lungs. Following exposure of neonatal mice to PM, IL22 levels increased, as did other AhR-dependent genes such as Cyp1a1. These responses returned to baseline and were no different from those of non-exposed controls as early as 4 days post-exposure. Importantly, IL22 expression is not increased following Flu infection of PM-exposed, but not vehicle-exposed, neonates; and our preliminary data suggest its expression is critical to host defense against Flu. PM exposure also altered microbial community structure and induced metabolite changes in the lungs. Because AhR responds to environmental stimuli including combustion-derived PM and microbial metabolites, we hypothesize that neonatal mice develop enhanced Flu-mediated airways disease following PM exposure due to insufficient IL22 activation. Aim 1 will test the hypothesis that neonates exposed to PM develop more severe disease upon Flu infection due to their failure to induce IL22. Aim 2 will determine how PM exposure during infancy alters the molecular machinery responsible for IL22 transcription following Flu infection. Based on existing literature and our preliminary data we further hypothesize that early life exposure to PM alters the epigenome resulting in a failure to mount protective immune responses against Flu infection. Aim 3 will define the role of airway microbiota and their metabolites in mediating the PM- enhanced Flu morbidity. We hypothesize that PM exposure disrupts the airway microbiota and decreases metabolites necessary for sustaining AhR activation and IL22 production. Completion of these studies will provide us with an understanding of the cellular, molecular, and metabolic mechanisms of PM-enhanced Flu disease and help identify pharmacologic targets for the treatment of environmentally-induced asthma exacerbations due to LRTI.
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