Carbon Dioxide Controls Fungal Fitness and Skin Tropism ofCandida auris

Abstract

AbstractThe pronounced skin tropism and pan-antifungal resistance traits of the fungal pathogenCandida aurisstand 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. aurisdebilitates efficient growth on native skin. Collectively, our findings highlight critical roles of the CSP inC. aurisskin 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) toC. aurismultidrug 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 withC. aurisskin tropism✓CSP acts through ectopic ROS response, cell wall architecture and membrane lipid function✓CSP is required forC. aurisfitness and efficient growth and colonization of skin tissuesResult contents✓Integrated omics reveals multidrug-resistant mechanisms inC. auris✓CO2-sensing controls amphotericin B resistance (AMBR) traits through Rca1 and Efg1✓The carbonic anhydrase Nce103 governs susceptibility to amphotericin B✓The CSP influences AMBRby maintaining reactive oxygen species homeostasis✓The CSP controls AMBRvia cell membrane and cell wall remodelling✓The CSP regulates fungal fitness through controlling energy metabolism✓C. aurisrequires the CSP for skin colonization