Project Summary: Last year in the United States, there were 1.3 million cases of pneumonia (excluding covid19). Worldwide, last year, there were 49 million cases respectively. Even after successful therapy, pneumonia and other severe infections are associated with >3-fold increased mortality risk due to increased cardiovascular disease, cancer, and recurrent infections. Preliminary evidence by our group and others have demonstrated that these severe infections induce detrimental premature epigenetic scars that accelerate age-associated epigenetic perturbations and induce pathologic inflammation and decrease immune responsiveness. While other studies have identified post-infectious premature aging, this study will be the first to identify which post-infectious premature aging epigenetic scars are associated with post-infectious mortality, inflammation and decreased immune responsiveness. We previously identified that post-infectious detrimental epigenetic scars last at least 6 months. Studies with longer-term follow up have confirmed these epigenetic scars are still present 82 weeks after resolution of the original insult. Therefore, we will follow participants with severe pneumonia for 24-months after completion of successful therapy and make use of cutting-edge single cell sequencing to clarify how these detrimental scars are persistently propagated. Our preliminary in vitro data demonstrates that infection induced premature epigenetic aging and immune perturbations can be mitigated by drugs that inhibit the TCA cycle such as metformin, everolimus, and metformin. This study will implement mechanistic studies to explore how inhibitors of the TCA can be used to alleviate post-infectious premature epigenetic scars and restore immune responsiveness.