Elucidating the roles of alveolar macrophage inflammation and self renewal during influenza infection

Summary Respiratory viral infections, such as influenza and SARS-CoV-2, pose significant public health challenges, particularly affecting older adults with severe outcomes and long-term health issues like Post-Acute Sequelae of SARS-CoV-2 (PASC). Alveolar macrophages (AMs), the primary macrophage population in the lungs, play crucial roles in lung defense and tissue repair, but can become pro-inflammatory during infections, leading to tissue damage. Our previous studies identified that TCF4 and β-catenin, key transcription factors in WNT signaling, have opposing effects on AM responses: TCF4 supports AM stem- like self-renewal, while β-catenin enhances inflammatory responses. Additionally, AMs from aged mice and humans exhibit "senescence-like" characteristics, likely contributing to adverse outcomes in the respiratory tract during aging. The aims of this grant are to elucidate the reciprocal regulation of TCF4 and β-catenin in dictating AM fate and function, and to investigate the roles of AM senescence, controlled by TCF4, in lung health and virus-associated acute and chronic diseases during aging. Furthermore, we aim to develop therapeutic strategies targeting TCF4 to treat age-related acute and chronic conditions following respiratory viral infections. The successful completion of this application will shed light on the molecular basis underlying the age-associated defects in host response to viral infection and could open the door for novel therapeutics for severe acute diseases and/or chronic lung sequelae after viral infection in aged individuals.