{"paper_id":"d5bc25de-8cd8-430c-b717-92cd231c8b7c","body_text":"Fungal melanin induces host lipid defense by rewiring macrophage metabolism | 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 Biological Sciences - Article Fungal melanin induces host lipid defense by rewiring macrophage metabolism Georgios Chamilos, Vassilis Nidris, Ioannis Morianos, Electra Nenedaki, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8936009/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Alveolar macrophages (AMs) employ specialized immunometabolic programs to counteract virulence mechanisms of airborne pathogens and confer host protection1. Mucormycosis is a life-threatening respiratory fungal infection that predominantly affects patients with metabolic abnormalities, especially diabetic ketoacidosis (DKA) 2, through poorly defined mechanisms. Unlike other fungi, Mucorales induce phagosome maturation arrest in AMs through persistent surface expression of melanin3,4, yet the host defense mechanisms that restrict fungal growth remain uncharacterized. Herein, we found that phagocytosis of Mucorales spores triggers the selective recruitment of Lipid Droplets (LDs) to the phagosome, through metabolic reprograming of AM metabolism toward oxidative phosphorylation (OXPHOS). Ca2+ sequestration by fungal melanin triggers this immunometabolic response in AMs by modulating mitochondria dynamics. LD targeting results in robust accumulation of host free fatty acids (FFAs) within intracellular Mucorales spores, leading to rapid mitochondrial fragmentation, suppression of aerobic glycolysis and fungal growth arrest. In DKA, nuclear stabilization of HIF1 inhibits mitochondrial function and OXPHOS-dependent LD targeting to the phagosome to promote fungal disease. Pharmacological inhibition or conditional deletion of HIF1 in AMs restores OXPHOS and protects against mucormycosis. Collectively, our findings define a melanin-driven immunometabolic defense program and reveal host and fungal metabolic vulnerabilities with important implications in pathogenesis and treatment of mucormycosis. Biological sciences/Immunology/Infectious diseases/Fungal infection Health sciences/Pathogenesis Alveolar macrophages lipid droplets melanin Mucorales Rhizopus mucormycosis acidosis diabetic ketoacidosis (DKA) Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryVideo4.mov Supplementary video 4 SupplementaryVideo5.mov Supplementary video 5 SupplementaryVideo2.mov Supplementary video 2 SupplementaryVideo12.mov Supplementary video 12 SupplementaryVideo1.mov Supplemenrary Video 1 SupplementaryVideo11.mov Supplementary video 11 SupplementaryVideo8.mov Supplementary video 8 SupplementaryTable1.xlsx Supplementary table 1 SupplementaryVideo13.mov Supplementary video 13 SupplementaryImage1.pptx Supplementary image 1 ExtendedDataFiguresMelaninAMmanuscript15.pdf Extended figure 1-5 SupplementaryVideo10.mov Supplementary video 10 SupplementaryVideo9.mov Supplementary video 9 SupplementaryVideo14.mov Supplementary video 14 SupplementaryVideo3.mov Supplementary video 3 SupplementaryVideo6.mov Supplementary video 6 SupplementaryVideo15.mov Supplementary video 15 SupplementaryVideo7.mov Supplementary video 7 Cite Share Download PDF Status: Under Review 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-8936009\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Biological Sciences - Article\",\"associatedPublications\":[],\"authors\":[{\"id\":597707944,\"identity\":\"f7d998e7-9dd5-4435-873d-33c1e0357868\",\"order_by\":0,\"name\":\"Georgios 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metabolism\",\"fulltext\":[],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":false,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":true,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":true,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":true,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"nature-portfolio\",\"isNatureJournal\":true,\"hasQc\":false,\"allowDirectSubmit\":false,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Nature Portfolio\",\"twitterHandle\":\"\",\"acdcEnabled\":false,\"dfaEnabled\":false,\"editorialSystem\":\"ejp\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"Alveolar macrophages, lipid droplets, melanin, Mucorales, Rhizopus, mucormycosis, acidosis, diabetic ketoacidosis (DKA)\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-8936009/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-8936009/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eAlveolar macrophages (AMs) employ specialized immunometabolic programs to counteract virulence mechanisms of airborne pathogens and confer host protection1. Mucormycosis is a life-threatening respiratory fungal infection that predominantly affects patients with metabolic abnormalities, especially diabetic ketoacidosis (DKA) 2, through poorly defined mechanisms. Unlike other fungi, Mucorales induce phagosome maturation arrest in AMs through persistent surface expression of melanin3,4, yet the host defense mechanisms that restrict fungal growth remain uncharacterized.\\u003c/p\\u003e\\n\\u003cp\\u003eHerein, we found that phagocytosis of Mucorales spores triggers the selective recruitment of Lipid Droplets (LDs) to the phagosome, through metabolic reprograming of AM metabolism toward oxidative phosphorylation (OXPHOS). Ca2+ sequestration by fungal melanin triggers this immunometabolic response in AMs by modulating mitochondria dynamics. LD targeting results in robust accumulation of host free fatty acids (FFAs) within intracellular Mucorales spores, leading to rapid mitochondrial fragmentation, suppression of aerobic glycolysis and fungal growth arrest. In DKA, nuclear stabilization of HIF1 inhibits mitochondrial function and OXPHOS-dependent LD targeting to the phagosome to promote fungal disease. Pharmacological inhibition or conditional deletion of HIF1 in AMs restores OXPHOS and protects against mucormycosis. Collectively, our findings define a melanin-driven immunometabolic defense program and reveal host and fungal metabolic vulnerabilities with important implications in pathogenesis and treatment of mucormycosis.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Fungal melanin induces host lipid defense by rewiring macrophage metabolism\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2026-03-04 08:18:08\",\"doi\":\"10.21203/rs.3.rs-8936009/v1\",\"editorialEvents\":[],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"nature-immunology\",\"isNatureJournal\":true,\"hasQc\":false,\"allowDirectSubmit\":false,\"externalIdentity\":\"ni\",\"sideBox\":\"Learn more about [Nature Immunology](http://www.nature.com/ni/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Nature Immunology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"ejp\",\"reportingPortfolio\":\"Nature Research\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"72d52d6c-ea2c-4759-9210-ffb2f252db70\",\"owner\":[],\"postedDate\":\"March 4th, 2026\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[{\"id\":63608002,\"name\":\"Biological sciences/Immunology/Infectious diseases/Fungal infection\"},{\"id\":63608003,\"name\":\"Health sciences/Pathogenesis\"}],\"tags\":[],\"updatedAt\":\"2026-03-04T08:18:08+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2026-03-04 08:18:08\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-8936009\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-8936009\",\"identity\":\"rs-8936009\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}