Calcineurin regulates morphological development, stress responses and virulence in Fonsecaea monophora.

Fonsecaea monophora is a major cause of chromoblastomycosis (CBM) in southern China. While calcineurin is known to be a virulence factor in several fungi, its role in F. monophora remains poorly understood. In this study, we characterized the function of calcineurin in F. monophora by examining mutants of the two calcineurin subunit genes (cnaA and cnaB). The mutants exhibited significant defects in conidiation, germination, morphogenesis (including the transformation into muriform cells), resistance to various stressors, and increased susceptibility to triazole drugs. Importantly, the mutants showed greater susceptibility to macrophage-mediated killing in vitro and reduced virulence in a mouse model. Interestingly, deletion of the potential transcription factor gene (crzA) did not produce similar phenotypic changes, suggesting that calcineurin regulates these processes maybe independently of crzA. Our findings advance the understanding of calcineurin's role in the morphology, antifungal resistance, and virulence of F. monophora. Given that the combination of itraconazole and tacrolimus has a synergistic effect on clinical strains, we propose that targeting calcineurin in combination with itraconazole may offer an effective therapeutic approach for CBM.