Monocyte-derived alveolar macrophages autonomously determine severe outcome of respiratory viral infection

Various lung insults can result in replacement of resident alveolar macrophages (AM) by bone marrow monocyte-derived (BMo)-AM. However, the dynamics of this process and its long-term consequences for respiratory viral infections remain unclear. Using several mouse models and a marker to unambiguously track fetal monocyte-derived (FeMo)-AM and BMo-AM, we established the kinetics and extent of replenishment and their function to recurrent influenza A virus (IAV) infection. A massive loss of FeMo-AM resulted in rapid replenishment by self-renewal of survivors, followed by the generation of BMo-AM. BMo-AM progressively outcompeted FeMo-AM over several months, and this was due to their increased glycolytic and proliferative capacity. The presence of both naïve and experienced BMo-AM conferred severe pathology to IAV infection, which was associated with a proinflammatory phenotype. Furthermore, upon aging of naïve mice, FeMo-AM were gradually replaced by BMo-AM, which contributed to IAV disease severity in a cell-autonomous manner. Together, our results suggest that the origin rather than training of AM determines long-term function to respiratory viral infection and provide an explanation for the increased severity of infection seen in the elderly.