Authors: Laura C. Ristow, Andrew J. Jezewski, Benjamin J. Chadwick, Mark A. Stamnes, Xiaorong Lin, Damian J. Krysan
Published: 2023-10-18
DOI: 10.1038/s41467-023-42318-y
Source: Full article
AbstractCryptococcusspp. are environmental fungi that first must adapt to the host environment before they can cause life-threatening meningitis in immunocompromised patients. Host CO2concentrations are 100-fold higher than the external environment and strains unable to grow at host CO2concentrations are not pathogenic. Using a genetic screening and transcriptional profiling approach, we report that the TOR pathway is critical forC. neoformansadaptation to host CO2partly through Ypk1-dependent remodeling of phosphatidylserine asymmetry at the plasma membrane. We also describe aC. neoformansABC/PDR transporter (PDR9) that is highly expressed in CO2-sensitive environmental strains, suppresses CO2-induced phosphatidylserine/phospholipid remodeling, and increases susceptibility to host concentrations of CO2. Interestingly, regulation of plasma membrane lipid asymmetry by the TOR-Ypk1 axis is distinct inC. neoformanscompared toS. cerevisiae. Finally, host CO2concentrations suppress theC. neoformanspathways that respond to host temperature (Mpk1) and pH (Rim101), indicating that host adaptation requires a stringent balance among distinct stress responses.