Modulation of epithelial memory by the microbiome

PROJECT SUMMARY PROJECT 2 The goal of Project 2 is to understand how age-related declines in lung immunity and antiviral response relate to corresponding changes in the epigenome and respiratory microbiome. Older adults have increased susceptibility to viral infection and adverse outcomes. Multiple factors contribute to this increased susceptibility, including changes in innate immune memory and consequent changes in interactions with commensal microbiota, which play an important role in the morphogenesis and maintenance of respiratory immunity. Numerous epigenetic changes have been associated with aging-related disease. Our overarching hypothesis is that age-related epigenetic changes in the lung epithelium are linked with an altered response to the commensal microbiome, leading to chronic inflammation and altered tissue immunity to respond to viral infection. In Project 1, we observed significant transcriptional differences in lung progenitors from older vs. younger individuals. We seek here to determine, using bulk and single-cell genome-wide chromatin accessibility assays of air-liquid interface (ALI) cultures developed from these older vs. younger lung progenitors, to what degree epigenetic modifications drive these transcriptional changes and which are associated with altered viral response (Aim 1). Then, we will investigate to what degree these aging-associated modifications affect interactions with microbial stimuli (Aim 2), stimulating old/young ALI cultures with genetically diverse microbes, examining phenotype and transcriptional response following colonization. Finally, we will investigate how the collective changes in epithelial immunity resulting from age and differential microbial response affect interactions with tissue-resident immune cells and collective influenza response (Aim 3), leveraging the Technology Development Project's models integrating alveolar macrophages into ALI cultures. We anticipate that these data will pinpoint microbial and epigenetic mechanisms contributing to lung immune aging, and how in turn these changes affect viral response.