Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.
Department of Plant Biology, University of Georgia, Athens, GA, 30602, USA.
Nat Commun. 2023 Oct 18;14(1):6587. doi: 10.1038/s41467-023-42318-y.
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 concentrations are 100-fold higher than the external environment and strains unable to grow at host CO 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 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-sensitive environmental strains, suppresses CO-induced phosphatidylserine/phospholipid remodeling, and increases susceptibility to host concentrations of CO. Interestingly, regulation of plasma membrane lipid asymmetry by the TOR-Ypk1 axis is distinct in C. neoformans compared to S. cerevisiae. Finally, host CO 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.
隐球菌属是环境真菌，它们必须首先适应宿主环境，然后才能在免疫功能低下的患者中引起危及生命的脑膜炎。宿主 CO 浓度比外部环境高 100 倍，无法在宿主 CO 浓度下生长的菌株没有致病性。我们通过遗传筛选和转录谱分析方法报告称，TOR 途径对于新生隐球菌适应宿主 CO 至关重要，部分原因是 Ypk1 依赖性重塑质膜上的磷脂酰丝氨酸不对称性。我们还描述了一种新生隐球菌 ABC/PDR 转运蛋白（PDR9），它在 CO 敏感的环境菌株中高度表达，抑制 CO 诱导的磷脂酰丝氨酸/磷脂重塑，并增加对宿主 CO 浓度的敏感性。有趣的是，TOR-Ypk1 轴对质膜脂质不对称性的调节在新生隐球菌与酿酒酵母中明显不同。最后，宿主 CO 浓度抑制了响应宿主温度（Mpk1）和 pH（Rim101）的新生隐球菌途径，表明宿主适应需要在不同的应激反应之间保持严格的平衡。
