Journal Article

Tricyclazole alleviates Fonsecaea pedrosoi-induced immune suppression of neutrophils by inhibiting DHN-melanin biosynthesis

Wang, Yuanyuan, Tan, Jingwen, Yang, Lianjuan, Yu, Qian, Li, Lulu, Li, Wei, Zheng, Chunjiao, Ni, Linan, Liu, Xiaoping

2026

Overview

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. ( ), the most common etiological agent of CBM, relies on its virulence factor DHN-melanin to evade host immune responses-especially by suppressing neutrophil function-further 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. This study aimed to investigate the effects of tricyclazole (TCZ) on and neutrophil antifungal responses, with a particular focus on its potential actions in inhibiting DHN-melanin synthesis and enhancing host oxidative immune mechanisms. We conducted assays to assess the effects of TCZ on melanin and fungal antioxidant enzymes, as well as reactive oxygen species (ROS) production and neutrophil extracellular traps (NETs) formation in human neutrophils. The mouse model was used to evaluate inflammatory responses, neutrophil-related markers, and fungal clearance. 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's ability to resist host oxidative stress but also reduces its capacity to evade immune recognition, creating conditions for subsequent immune clearance. 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's 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's therapeutic efficacy, demonstrating its potential to mitigate inflammatory tissue damage while achieving effective fungal eradication. This study reveals a novel mechanism by which TCZ counteracts -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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animal models / Animals / Antibodies / Antifungal Agents - pharmacology / Antioxidants / Biosynthesis / Cell activation / chromoblastomycosis / Chromoblastomycosis - drug therapy / Chromoblastomycosis - immunology / Chromoblastomycosis - microbiology / Chromomycosis / Chronic infection / Dermatology / DHN-melanin synthesis / Disease Models, Animal / Disease resistance / Extracellular Traps - drug effects / Extracellular Traps - metabolism / Female / Fonsecaea - drug effects / Fonsecaea - immunology / Fonsecaea - metabolism / Fonsecaea - pathogenicity / Fonsecaea pedrosoi / Fungal infections / Humans / Immune clearance / Immune response / Immunomodulation / Immunoregulation / Immunosuppression / Inflammation / Laboratory animals / Leukocytes (neutrophilic) / Melanin / Melanins - antagonists & inhibitors / Melanins - biosynthesis / Mice / Naphthols / NETs (neutrophil extracellular traps) / Neutrophils / Neutrophils - drug effects / Neutrophils - immunology / Neutrophils - microbiology / Original Research / Oxidative Stress / Pathogens / Reactive oxygen species / Reactive Oxygen Species - metabolism / Thiazoles - pharmacology / tricyclazole / Virulence factors