Sterol Remodeling in Fusarium oxysporum Drives Mammalian Virulence through Pyroptosis and Chemokine Suppression

Sterol Remodeling in Fusarium oxysporum Drives Mammalian Virulence through Pyroptosis and Chemokine Suppression | 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 Article Sterol Remodeling in Fusarium oxysporum Drives Mammalian Virulence through Pyroptosis and Chemokine Suppression Neta Shlezinger, Marina Rocha, John Adeoye, Hilla Hayby, Siyuan Wu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9124666/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 Members of the Fusarium oxysporum species complex are globally distributed soil fungi and plant pathogens that increasingly cause severe and often treatment-refractory human infections. Because clinical and non-clinical isolates arise from overlapping ecological reservoirs, the biological features that contribute to enhanced virulence in mammalian hosts remain incompletely defined. Here, we identify remodeling of ergosterol homeostasis as a distinguishing characteristic of clinically derived isolates, which displayed increased ergosterol biosynthetic activity, elevated extracellular ergosterol release, reduced azole accumulation, and increased pathogenicity in a murine infection model. Functionally, heightened sterol flux promoted caspase-1–dependent macrophage pyroptosis while selectively suppressing chemokine production through IL-10/TGF-β–associated pathways, resulting in impaired neutrophil recruitment despite robust proinflammatory cytokine induction. We propose that enhanced sterol biosynthesis, potentially favored under azole exposure, amplifies pathogenic potential in mammalian hosts. These findings redefine ergosterol as an immunomodulatory virulence determinant linking sterol metabolism, host adaptation, and disease severity. Biological sciences/Microbiology/Fungi/Fungal immune evasion Biological sciences/Immunology/Infectious diseases/Fungal infection Full Text Additional Declarations There is NO Competing Interest. 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-9124666","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":606791447,"identity":"4cd8c3bc-d5d4-4579-bb82-558fe914e256","order_by":0,"name":"Neta Shlezinger","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-0005-0756","institution":"The Hebrew University","correspondingAuthor":true,"prefix":"","firstName":"Neta","middleName":"","lastName":"Shlezinger","suffix":""},{"id":606791448,"identity":"a4a06dc5-3f10-4e71-a0e2-1057c09498c8","order_by":1,"name":"Marina Rocha","email":"","orcid":"https://orcid.org/0000-0003-4988-7629","institution":"Koret School of Veterinary Medicine, The Robert H. 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Because clinical and non-clinical isolates arise from overlapping ecological reservoirs, the biological features that contribute to enhanced virulence in mammalian hosts remain incompletely defined. Here, we identify remodeling of ergosterol homeostasis as a distinguishing characteristic of clinically derived isolates, which displayed increased ergosterol biosynthetic activity, elevated extracellular ergosterol release, reduced azole accumulation, and increased pathogenicity in a murine infection model. Functionally, heightened sterol flux promoted caspase-1–dependent macrophage pyroptosis while selectively suppressing chemokine production through IL-10/TGF-β–associated pathways, resulting in impaired neutrophil recruitment despite robust proinflammatory cytokine induction. We propose that enhanced sterol biosynthesis, potentially favored under azole exposure, amplifies pathogenic potential in mammalian hosts. 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