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

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.

This study aimed to investigate how Fonsecaea monophora (F. monophora) reprograms polymorphonuclear myeloid-Derived suppressor cells (PMN-MDSCs) to suppress T-cell immunity.

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.

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.

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.