Carbon Dioxide Controls Fungal Fitness and Skin Tropism of Candida auris
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The pronounced skin tropism and pan-antifungal resistance traits of the fungal pathogen Candida auris stand out as a serious health threat. Here, we show that a carbonic sensing pathway (CSP) promotes development of resistance to amphotericin B through a reactive oxygen species (ROS) response, as well as ectopic cell wall and membrane lipid homeostasis. Mechanistically, the transcription factor Rca1 acts in cooperation with Efg1 to control the expression and activity of the carbonic anhydrase Nce103 as a key effector component. The conversion of carbon dioxide to bicarbonate provides a direct link to energy metabolism, facilitating colonization and growth on skin tissues. Native mouse and human skin models unequivocally show that the CSP is essential for maintaining skin tropism as well as fungal fitness. Curiously, upon ablation of Rca1 and Efg1, C. auris debilitates efficient growth on native skin. Collectively, our findings highlight critical roles of the CSP in C. auris skin tropism and antifungal drug resistance. The work suggests therapeutic options for disrupting skin colonization and thus preventing infections.
Highlights
Proteo-transcriptomics links a carbonic sensing pathway (CSP) to C. auris multidrug resistance
The Nce103 carbonic anhydrase controls drug resistance as a key component of the CSP
The transcription factors Rca1 and Efg1 control Nce103 and link CSP with C. auris skin tropism
CSP acts through ectopic ROS response, cell wall architecture and membrane lipid function
CSP is required for C. auris fitness and efficient growth and colonization of skin tissues
Result contents
Integrated omics reveals multidrug-resistant mechanisms in C. auris
CO 2 -sensing controls amphotericin B resistance (AMB R ) traits through Rca1 and Efg1
The carbonic anhydrase Nce103 governs susceptibility to amphotericin B
The CSP influences AMB R by maintaining reactive oxygen species homeostasis
The CSP controls AMB R via cell membrane and cell wall remodelling
The CSP regulates fungal fitness through controlling energy metabolism
C. auris requires the CSP for skin colonization
