PmZapA orchestrates zinc homeostasis and pleiotropic stress responses to drive pathogenicity in Talaromyces marneffei

Zinc homeostasis is critical for pathogenic microbes during their interactions with hosts. In Aspergillus nidulans, the transcription factor ZapA serves as a key regulator of zinc uptake. However, the function of ZapA in the thermally dimorphic pathogen Talaromyces marneffei remains largely unexplored. In this study, we identified and characterized the ZapA homolog in T. marneffei. Our results demonstrate that PmZapA acts as a master regulator of zinc homeostasis by directly controlling the expression of the zinc transporter encoding genes. Deletion of PmzapA severely impaired growth under Zinc – conditions and reduced pigment production. Notably, in a Galleria mellonella larval infection model, the ΔPmzapA strain exhibited significantly attenuated virulence. However, the reduced pathogenicity was not solely attributable to defective zinc transport, as additional pleiotropic effects were detected. Specifically, the ΔPmzapA strain showed impaired reactive oxygen species (ROS) clearance capability, as well as increased susceptibility to cell wall stress and alkaline pH. Integrated RNA-seq and ChIP-seq analysis revealed that PmZapA governs a broad regulatory network, directly and indirectly modulating pathways involved in redox homeostasis, secondary metabolite biosynthesis, as well as carbon metabolism. Collectively, our work identifies PmZapA as a novel virulence determinant in T. marneffei.