{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:21:38Z","timestamp":1789428098083,"version":"build-2803163510"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"\n Introduction<\/jats:title>\n \n Chromoblastomycosis (CBM) is a chronic cutaneous infection caused by dematiaceous fungi, characterized by therapeutic challenges such as difficulty in pathogen clearance and high recurrence rates.\n Fonsecaea pedrosoi<\/jats:italic>\n (\n F. pedrosoi<\/jats:italic>\n ), the most common etiological agent of CBM, relies on its virulence factor DHN-melanin to evade host immune responses\u2014especially by suppressing neutrophil function\u2014further contributing to disease persistence and treatment resistance. Thus, we intended to explore therapeutic approaches that target both fungal virulence mechanisms and host immune regulation to overcome the clinical hurdles of CBM.\n <\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n \n This study aimed to investigate the effects of tricyclazole (TCZ) on\n F. pedrosoi<\/jats:italic>\n and neutrophil antifungal responses, with a particular focus on its potential actions in inhibiting DHN-melanin synthesis and enhancing host oxidative immune mechanisms.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We conducted\n in vitro<\/jats:italic>\n assays to assess the effects of TCZ on\n F. pedrosoi<\/jats:italic>\n melanin and fungal antioxidant enzymes, as well as reactive oxygen species (ROS) production and neutrophil extracellular traps (NETs) formation in human neutrophils. The\n in vivo<\/jats:italic>\n mouse model was used to evaluate inflammatory responses, neutrophil-related markers, and fungal clearance.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In vitro<\/jats:italic>\n tests showed TCZ dose-dependently inhibited fungal DHN-melanin synthesis and disrupted the antioxidant enzyme system (including superoxide dismutase and catalase); this effect not only weakens the fungus\u2019s ability to resist host oxidative stress but also reduces its capacity to evade immune recognition, creating conditions for subsequent immune clearance.\n In vitro<\/jats:italic>\n co-culture models revealed that TCZ significantly enhanced neutrophil ROS production and NET formation; this strengthens the oxidative killing function of neutrophils, directly counteracting the immunosuppressive effect of DHN-melanin on neutrophils and improving the host\u2019s ability to eliminate pathogens. In a mouse infection model, TCZ treatment significantly alleviated pedal inflammation, reduced neutrophil activation markers, and completely eliminated fungal colonization; these results validate TCZ\u2019s\n in vivo<\/jats:italic>\n therapeutic efficacy, demonstrating its potential to mitigate inflammatory tissue damage while achieving effective fungal eradication.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n This study reveals a novel mechanism by which TCZ counteracts\n F. pedrosoi<\/jats:italic>\n -mediated suppression of neutrophil antifungal effector functions, particularly oxidative burst and NET formation, thereby facilitating fungal clearance in CBM. These findings provide a novel strategy for CBM treatment by integrating immunomodulation with antifungal therapy.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fcimb.2025.1697287","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T08:10:10Z","timestamp":1768205410000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Tricyclazole alleviates Fonsecaea pedrosoi-induced immune suppression of neutrophils by inhibiting DHN-melanin biosynthesis"],"prefix":"10.3389","volume":"15","author":[{"given":"Chunjiao","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linan","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianjuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/0003-2697(71)90370-8","article-title":"Superoxide dismutase: improved assays and an assay applicable to acrylamide gels","volume":"44","author":"Beauchamp","year":"1971","journal-title":"Anal. Biochem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s11046-005-0228-6","article-title":"Inhibition of nitric oxide production by macrophages in chromoblastomycosis: a role for Fonsecaea pedrosoi melanin","volume":"161","author":"Bocca","year":"2006","journal-title":"Mycopathologia"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.540064","article-title":"Fonsecaeapedrosoi conidia and hyphae activate neutrophils distinctly: requirement of TLR-2 and TLR-4 in neutrophil effector functions","volume":"11","author":"Breda","year":"2020","journal-title":"Front. Immunol."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/jof7010003","article-title":"Immune sensing and potential immunotherapeutic approaches to control chromoblastomycosis","volume":"7","author":"Breda","year":"2020","journal-title":"J. F. (Bs)"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1126\/science.1092385","article-title":"Neutrophil extracellular traps kill bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1590\/abd1806-4841.20187321","article-title":"Chromoblastomycosis: an etiological, epidemiological, clinical, diagnostic, and treatment update","volume":"93","author":"Brito","year":"2018","journal-title":"Bras. Dermatol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1834","DOI":"10.1016\/j.freeradbiomed.2010.09.016","article-title":"Intracellular generation of superoxide by the phagocyte NADPH oxidase: how, where, and what for","volume":"49","author":"Bylund","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1038\/ni.2984","article-title":"Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion","volume":"15","author":"Chen","year":"2014","journal-title":"Nat. Immunol."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2019.104438","article-title":"The ADME profile of the fungicide tricyclazole in rodent via the oral route: A critical review for human health safety assessment","volume":"108","author":"Corvaro","year":"2019","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1002\/jemt.20260","article-title":"Inhibition of melanin synthesis pathway by tricyclazole increases susceptibility of Fonsecaea pedrosoi against mouse macrophages","volume":"68","author":"Cunha","year":"2005","journal-title":"Microsc. Res. Tech."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-10-80","article-title":"Melanin in Fonsecaea pedrosoi: a trap for oxidative radicals","volume":"10","author":"Cunha","year":"2010","journal-title":"BMC Microbiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/ni.2260","article-title":"The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss","volume":"13","author":"Eskan","year":"2012","journal-title":"Nat. Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1002\/jemt.20344","article-title":"Effects of tricyclazole (5-methyl-1,2,4-triazol[3,4] benzothiazole), a specific DHN-melanin inhibitor, on the morphology of Fonsecaea pedrosoi conidia and sclerotic cells","volume":"69","author":"Franzen","year":"2006","journal-title":"Microsc. Res. Tech."},{"key":"B14","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.dib.2015.12.012","article-title":"Data supporting the spectrophotometric method for the estimation of catalase activity","volume":"6","author":"Hadwan","year":"2016","journal-title":"Data Brief"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3791\/60397","article-title":"Measuring phagocytosis of Aspergillus fumigatus conidia by human leukocytes using flow cytometry","volume":"154","author":"Hartung","year":"2019","journal-title":"J. Vis. Exp"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e0054621","DOI":"10.1128\/aac.00546-21","article-title":"Effect of melanin biosynthesis inhibition on the antifungal susceptibility of chromoblastomycosis agents","volume":"65","author":"Heidrich","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/j.bbagen.2007.12.004","article-title":"Redox control and oxidative stress in yeast cells","volume":"1780","author":"Herrero","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1093\/cvr\/cvab329","article-title":"Neutrophil extracellular traps: from physiology to pathology","volume":"118","author":"Hidalgo","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1002\/jobm.202000664","article-title":"Melanin and chromoblastomycosis agents: Characterization, functions, and relation with antifungals","volume":"61","author":"Koehler","year":"2021","journal-title":"J. Bas. Microbiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1827","DOI":"10.1111\/jam.14076","article-title":"Effect of tricyclazole on morphology, virulence and gene expression of Aspergillus aculeatus for management of soft rot disease in peach","volume":"125","author":"Kong","year":"2018","journal-title":"J. Appl. Microbiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s11274-014-1756-3","article-title":"Effect of tricyclazole on morphology, virulence and enzymatic alterations in pathogenic fungi bipolaris sorokiniana for management of spot blotch disease in barley","volume":"31","author":"Kumar","year":"2015","journal-title":"World J. Microbiol. Biotechnol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e0018925","DOI":"10.1128\/mbio.00189-25","article-title":"Mechanisms and immune crosstalk of neutrophil extracellular traps in response to infection","volume":"16","author":"Liu","year":"2025","journal-title":"mBio"},{"key":"B23","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1016\/j.micinf.2005.01.006","article-title":"Cytokines and lymphocyte proliferation in patients with different clinical forms of chromoblastomycosis","volume":"7","author":"Mazo F\u00e1vero Gimenes","year":"2005","journal-title":"Microbes Infect."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00373","article-title":"Neutrophils to the ROScue: Mechanisms of NADPH oxidase activation and bacterial resistance","volume":"7","author":"Nguyen","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1007\/s00604-024-06682-w","article-title":"Flexible SERS chips for rapid on-site detection of tricyclazole pesticide in agricultural products","volume":"191","author":"Pham","year":"2024","journal-title":"Mikrochim Acta"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2021.112493","article-title":"1,8-dihydroxy naphthalene (DHN) - melanin confers tolerance to cadmium in isolates of melanised dark septate endophytes","volume":"222","author":"Potisek","year":"2021","journal-title":"Ecotoxicol Environ. Saf."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1111\/ijd.14185","article-title":"Chromoblastomycosis: clinical experience and review of literature","volume":"57","author":"Queir\u00f3z","year":"2018","journal-title":"Int. J. Dermatol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1128\/cmr.00032-16","article-title":"Chromoblastomycosis","volume":"30","author":"Queiroz-Telles","year":"2017","journal-title":"Clin. Microbiol. Rev."},{"key":"B29","doi-asserted-by":"publisher","first-page":"9149","DOI":"10.3390\/ijms21239149","article-title":"Use of H2O2 to cause oxidative stress, the catalase issue","volume":"21","author":"Ransy","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2012.00093","article-title":"Bir1 deletion causes malfunction of the spindle assembly checkpoint and apoptosis in yeast","volume":"2","author":"Ren","year":"2012","journal-title":"Front. Oncol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/bf01146200","article-title":"The in vitro susceptibility of Fonsecaea pedrosoi to activated macrophages","volume":"126","author":"Rozental","year":"1994","journal-title":"Mycopathologia"},{"key":"B32","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1080\/02681219680000551","article-title":"Fine structure and cytochemical study of the interaction between Fonsecaea pedrosoi and rat polymorphonuclear leukocyte","volume":"34","author":"Rozental","year":"1996","journal-title":"J. Med. Vet. Mycol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1111\/j.1574-6976.2007.00077.x","article-title":"Biology and pathogenesis of Fonsecaea pedrosoi, the major etiologic agent of chromoblastomycosis","volume":"31","author":"Santos","year":"2007","journal-title":"FEMS Microbiol. Rev."},{"key":"B34","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1007\/s00018-022-04353-8","article-title":"Oxidative stress response pathways in fungi","volume":"79","author":"Yaakoub","year":"2022","journal-title":"Cell Mol. Life Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1007\/s11046-012-9588-x","article-title":"Melanin in a meristematic mutant of Fonsecaea monophora inhibits the production of nitric oxide and Th1 cytokines of murine macrophages","volume":"175","author":"Zhang","year":"2013","journal-title":"Mycopathologia"},{"key":"B36","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1007\/s12016-025-09040-7","article-title":"Implication of immunobiological function of melanocytes in dermatology","volume":"68","author":"Zhang","year":"2025","journal-title":"Clin. Rev. Allergy Immunol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1697287\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T08:10:10Z","timestamp":1768205410000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1697287\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,12]]},"references-count":36,"alternative-id":["10.3389\/fcimb.2025.1697287"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2025.1697287","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,12]]},"article-number":"1697287"}}