Abstract
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.