Cryptococcus neoformans adapts to the host environment through TOR-mediated remodeling of phospholipid asymmetry

Cryptococcus spp. are environmental fungi that first must adapt to the host environment before they can cause life-threatening meningitis in immunocompromised patients. Host CO(2) concentrations are 100-fold higher than the external environment and strains unable to grow at host CO(2) concentrations are not pathogenic. Using a genetic screening and transcriptional profiling approach, we report that the TOR pathway is critical for C. neoformans adaptation to host CO(2) partly through Ypk1-dependent remodeling of phosphatidylserine asymmetry at the plasma membrane. We also describe a C. neoformans ABC/PDR transporter (PDR9) that is highly expressed in CO(2)-sensitive environmental strains, suppresses CO(2)-induced phosphatidylserine/phospholipid remodeling, and increases susceptibility to host concentrations of CO(2). Interestingly, regulation of plasma membrane lipid asymmetry by the TOR-Ypk1 axis is distinct in C. neoformans compared to S. cerevisiae. Finally, host CO(2) concentrations suppress the C. neoformans pathways that respond to host temperature (Mpk1) and pH (Rim101), indicating that host adaptation requires a stringent balance among distinct stress responses.