Infection history and cellular origin shape long-term alveolar macrophage reprogramming 2301676

Abstract Introduction Alveolar macrophages (AMs) are essential sentinels of the lung, maintaining alveolar homeostasis through surfactant clearance, pathogen removal, and regulation of inflammation and tissue repair. During viral infection, circulating monocytes are recruited to the lung and may give rise to monocyte-derived AMs (Mo-AMs). Whether long-term differences between resident and Mo-AMs reflect intrinsic ontogeny or virus-specific imprinting remains unclear. Methods We integrated monocyte fate mapping with phenotypic, transcriptomic, and epigenetic profiling to delineate the relative contributions of cellular origin and virus-specific imprinting on AMs following infection with DNA (Murid herpesvirus 4, MuHV-4; Mouse adenovirus 1, MAV-1) and RNA (Influenza A virus PR8; Pneumonia virus of mice, PVM) viruses. Results Our results show that Mo-AMs emerge and persist long-term in a virus-specific proportion, with monocyte contribution to the AM compartment increasing over time. By 60 days post-infection, Mo-AMs acquire a transcriptomic profile broadly similar to resident AMs but retain enhanced expression of gene programs associated with fibrosis, activation, and metabolic reprogramming, while sustaining reduced expression of canonical resident AM markers. Transcriptomic profiling further revealed that infiltrating monocytes and repair-phase macrophages display virus-specific signatures, with subsets of these programs maintained long-term in AMs. MuHV-4 and MAV-1 infections elicited sustained interferon signaling, whereas PR8 preferentially maintained extracellular matrix—associated pathways accompanied by Stat3 and Srebf2 induction in AMs. PVM partially shared transcriptional features with MuHV-4 and MAV-1, yet exhibited distinct chromatin remodeling, highlighting virus-specific imprinting of the AM compartment. Conclusion Thus, infection history, more than ontogeny, imprints lasting transcriptional and epigenetic programs in Mo-AMs, potentially reshaping lung homeostasis and influencing disease susceptibility. Funding Source Fonds de la Recherche Scientifique (FNRS), European Research Council (ERC) Topic Categories Viral Immunology (VIR)