{"paper_id":"cc40dbc7-8ef5-48fa-bf1d-d844dcb2b03c","body_text":"Schistosoma immune evasion of NETosis is reversed by aryl hydantoin Ro 13-3978 | 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 Schistosoma immune evasion of NETosis is reversed by aryl hydantoin Ro 13-3978 Tiffany Bouchery, Rory Doolan, Vanessa Trefzer, Dovran Ovezgeldiyev, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7453538/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 Schistosomiasis remains a major global health burden, with praziquantel as the only available treatment despite limitations such as reduced efficacy against juvenile stages. Aryl hydantoins such as Ro 13-3978 (AR02) and its derivative AR102, exhibit potent in vivo activity against all major human schistosome species, yet lack direct in vitro efficacy, suggesting a host-directed mechanism. Here, we identify neutrophils as critical mediators of aryl hydantoin activity. In a murine model of Schistosoma mansoni infection, neutrophil depletion or enzymatic degradation of extracellular DNA significantly impaired drug efficacy. Using human neutrophil co-cultures, we show that schistosomes suppress extracellular trap formation (NETosis), but aryl hydantoins restore this response without directly inducing NETs. Proteomics revealed compound-dependent modulation of neutrophil activation pathways, including chromatin remodeling and degranulation, specifically in the presence of parasite-derived products. Compound effects were limited to PMA-induced NETosis, implicating a pathway downstream of ROS production. While the precise molecular target remains elusive, our findings provide key mechanistic insight into a unique host-directed anthelmintic strategy, highlighting a neutrophil-dependent mode of action that restores NETosis suppressed by schistosomes -offering a promising pathway for immunomodulatory anti-parasitic therapies. Health sciences/Diseases/Infectious diseases/Parasitic infection Biological sciences/Immunology/Immune evasion Biological sciences/Immunology/Innate immune cells/Granulocytes/Neutrophils Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Table1PMAModel1results.xlsx Table 1 Table2PMAModel2results.xlsx Table 2 Table3IONOModel2results.xlsx Table 3 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. 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-7453538\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":505745894,\"identity\":\"ecbb399d-81c4-4498-986a-5078ffb1571c\",\"order_by\":0,\"name\":\"Tiffany 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