Autophagy drives immunosuppressive function in Fonsecaea monophora-induced PMN-MDSCs in chromoblastomycosis.

BACKGROUND: Chromoblastomycosis (CBM) is a chronic subcutaneous infection caused by the dematiaceous fungi. The chronic persistence of CBM brings great distress to patients. Myeloid-derived suppressor cells (MDSCs) are implicated in immunosuppression during chronic infections, yet the role of MDSCs in CBM remains elusive. OBJECTIVES: This study aimed to investigate how Fonsecaea monophora (F. monophora) reprograms polymorphonuclear myeloid-Derived suppressor cells (PMN-MDSCs) to suppress T-cell immunity. METHODS: We detected CD11b+CD15+ PMN-MDSCs in CBM patient lesions via immunofluorescence. Using the HL60 cell model, we examined the induction of PMN-MDSCs by F. monophora conidia and assessed the immunosuppressive function through T-cell proliferation assay (EdU assay) and Annexin V/PI apoptosis staining. Underlying mechanisms were probed through RNA-sequencing, analysis of autophagic flux (LC3B, p62), and measurement of reactive oxygen species. Interventions involved the autophagy activator rapamycin and the ROS scavenger N-acetylcysteine. RESULTS: PMN-MDSCs were significantly enriched in CBM lesions compared to healthy and acute infection controls. F. monophora conidia effectively induced the differentiation of functional PMN-MDSCs in vitro, which suppressed T-cell proliferation and viability. In conidia-induced PMN-MDSCs, transcriptomic and functional analyses revealed that immunosuppression is mediated through impaired autophagic flux and subsequent ROS accumulation, rather than the classical ARG1/NOS2 pathways. Crucially, the immunosuppressive effects were reversed by interventions targeting autophagy or ROS. CONCLUSION: F. monophora drives PMN-MDSCs-mediated immunosuppression through an autophagy impairment-ROS accumulation axis, providing a mechanistic basis for CBM chronicity and a therapeutic strategy targeting MDSCs.