Type-2-immune history imprints local training in nerve-airway associated interstitial macrophages (NAMs) for disease tolerance during respiratory viral infection

Severe respiratory viral disease varies widely among individuals and often reflects immunopathology rather than inadequate pathogen control, suggesting that prior immune history can prime the lung’s inflammatory–regulatory balance to promote disease tolerance. Here we show that nerve- and airway-associated macrophages (NAMs), a subset of interstitial macrophages expand following type 2 inflammation induced by Nippostrongylus brasiliensis. We hypothesized that NAMs acquire epigenetically imprinted trained immunity and tested this in a heterologous challenge model in which mice infected with Nippostrongylus brasiliensis were challenged 4–6 weeks later with lethal H1N1 influenza. Remarkably, all Nb-conditioned mice survived, whereas all unconditioned controls succumbed by days 5–6 post-infection. Protection occurred without improved viral burden or enhanced T cell responses, and instead tracked with reduced immunopathology, amplified type 2 cues, increased efferocytosis and accelerated tissue repair. Using NAM-DTR mice, we show that conditioned NAMs are necessary and sufficient for protection: depletion or replacement with unconditioned NAMs abrogated survival, whereas adoptive transfer of conditioned NAMs conferred tolerance without enhancing viral clearance. Genomic analyses implicated an IL-4–STAT6–PPARγ and Arginase-1 chromatin program that imprints a pro-resolving and reparative NAM state driving programs of tissue repair, type 2 immunity and efferocytosis during lethal respiratory viral infections. Finally, meta-analysis of human lung single-cell atlases from healthy, IPF and COPD cohorts indicated that reparative NAM-like programs aligned with fibrotic remodeling in IPF but diverged in COPD, supporting context-dependent consequences of sustained repair states. These findings establish local trained immunity in lung-resident macrophages as a mechanism of disease tolerance and a therapeutic entry point for severe inflammatory respiratory infections.