Project 4: Epigenetic modifiers of regulatory T cell function following viral pneumonia

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PROJECT SUMMARY/ABSTRACT – ESI-LED PROJECT 4 Influenza and COVID-19 exert a disproportionate impact on older patients. Influenza A virus and SARS-CoV-2 cause severe viral pneumonia, injuring the lung to induce the acute respiratory distress syndrome (ARDS), for which anti-viral therapies have limited efficacy and ICU interventions remain supportive. Older patients with virus- induced ARDS experience slow recovery, leading to protracted ICU stays that often herald the compounding multi-morbidity and functional limitation observed among elderly survivors of severe respiratory infection. We reason that activation of youthful resolution and repair pathways in older patients with severe viral pneumonia will potentiate recovery to extend the health-span of older ICU survivors. CD4+Foxp3+ regulatory T (Treg) cells coordinate resolution and repair following experimental acute lung injury. These cells appear in the alveolar spaces of patients with ARDS and display epigenetic and transcriptional signatures predicted by murine experiments. In contrast with young mice, Treg cells from aged mice exhibit a cell-autonomous impairment in pro-recovery function following influenza and fail to upregulate the epithelial growth factor amphiregulin. Mechanistically, epigenetic alterations in DNA methylation signatures represent a hallmark aging process that modulates Treg cell function, and Treg cells from aged mice and mice with genomic instability-induced premature aging display a striking DNA hypermethylation signature compared with Treg cells from young mice. DNA methyltransferase (DNMT) activity and the DNMT adapter Uhrf1 mediate DNA methylation signatures in Treg cells, but whether these factors induce DNA hypermethylation in Treg cells during normal and genomic instability- induced aging to impair Treg cell pro-recovery function following viral pneumonia in aged hosts remains unknown. We hypothesize that DNMT activity and Uhrf1 induce DNA hypermethylation in Treg cells during aging to impair Treg cell reparative function following severe viral pneumonia in older hosts. We propose three Specific Aims, which use cutting-edge murine systems, a translational human case-control study, and novel computational platforms to test our hypothesis. Aim 1 will reveal whether DNMT activity or Uhrf1 is necessary to induce DNA hypermethylation in Treg cells during aging. In Aim 2 we will determine whether transient loss of DNMT activity or Uhrf1 in Treg cells during recovery from influenza restores the transcriptional programs and amphiregulin-dependent function present in youth but lost with aging. Aim 3 will elucidate the association between age, alveolar Treg cell DNA methylation signature, and 30-day mortality in selected patients with severe influenza A or COVID-19 viral pneumonia. Our proposal will establish causal evidence linking drug-targetable mechanisms to detailed physiologic readouts. Elucidating these causal links will enable the development of pro- recovery therapeutic approaches for severe influenza, COVID-19, and other causes of ARDS in older patients.