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

Type-2-immune history imprints local training in nerve-airway associated interstitial macrophages (NAMs) for disease tolerance during respiratory viral infection | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Type-2-immune history imprints local training in nerve-airway associated interstitial macrophages (NAMs) for disease tolerance during respiratory viral infection Payal Damani-Yokota, Yavor Yordanov, Eduardo D. Bernier, Chaitra Sreenivasaiah, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8780633/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version 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. Immunology macrophages trained immunity NAMs innate immune memory disease tolerance efferocytosis type 2 immunity tissue-repair Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8780633","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":585958517,"identity":"e0b7b7eb-2ed5-419f-b057-eddc2659aaed","order_by":0,"name":"Payal Damani-Yokota","email":"","orcid":"https://orcid.org/0000-0001-5168-2329","institution":"NYU Langone School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Payal","middleName":"","lastName":"Damani-Yokota","suffix":""},{"id":585958519,"identity":"33e843cb-82dc-4dd4-bfa6-0186c00e928f","order_by":1,"name":"Yavor Yordanov","email":"","orcid":"","institution":"Radbound University","correspondingAuthor":false,"prefix":"","firstName":"Yavor","middleName":"","lastName":"Yordanov","suffix":""},{"id":585958521,"identity":"4cd7d66a-5638-4310-8e8f-b1830932d9c8","order_by":2,"name":"Eduardo D. 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Here we show that nerve- and airway-associated macrophages (NAMs), a subset of interstitial macrophages expand following type 2 inflammation induced by \u003cem\u003eNippostrongylus brasiliensis\u003c/em\u003e. \u0026nbsp;We hypothesized that NAMs acquire epigenetically imprinted trained immunity and tested this in a heterologous challenge model in which mice infected with \u003cem\u003eNippostrongylus brasiliensis\u003c/em\u003ewere challenged 4–6 weeks later with lethal H1N1 influenza. Remarkably, all \u003cem\u003eNb\u003c/em\u003e-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. 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