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 CO₂ concentrations are 100-fold higher than the external environment and strains unable to grow at host CO₂ 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 CO₂ 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 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 in C. neoformans compared to S. cerevisiae. Finally, host CO₂ 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.