SRP373103 PRJNA834032 GSE202000 Monocyte-derived alveolar macrophages autonomously determine severe outcome of respiratory viral infection [bulk RNA-seq] Various lung insults can result in replacement of resident alveolar macrophages (AM) by blood 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 virus (IAV) infection. Massive loss of FeMo-AM resulted in rapid replenishment by self-renewal of survivors followed by generation of BMo-AM, which progressively outcompeted FeMo-AM over several months due to 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 pro-inflammatory phenotype. Furthermore, upon aging of naïve mice, FeMo-AM are gradually replaced by BMo-AM, which contribute to IAV disease severity in a cell autonomous manner. Taken together, our results suggest that origin rather than training of AM determines long-term function to respiratory viral infection and provide an explanation for increased severity in elderly. Overall design: Comparative gene expression profiling analysis of RNA-seq data from alveolar macrophages differentiated from different precursor cells or after infection. GSE202000 pubmed 35776802 parent_bioproject PRJNA834025