Qu Xianya, Bhalla Kabir, Horianopoulos Linda C, Hu Guanggan, Alcázar Magaña Armando, Foster Leonard J, Roque da Silva Leandro Buffoni, Kretschmer Matthias, Kronstad James W
The Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
Front Fungal Biol. 2024 Aug 14;5:1447588. doi: 10.3389/ffunb.2024.1447588. eCollection 2024.
There is an urgent need for new antifungal drugs to treat invasive fungal diseases. Unfortunately, the echinocandin drugs that are fungicidal against other important fungal pathogens are ineffective against , the causative agent of life-threatening meningoencephalitis in immunocompromised people. Contributing mechanisms for echinocandin tolerance are emerging with connections to calcineurin signaling, the cell wall, and membrane composition. In this context, we discovered that a defect in phosphate uptake impairs the tolerance of to the echinocandin caspofungin. Our previous analysis of mutants lacking three high affinity phosphate transporters revealed reduced elaboration of the polysaccharide capsule and attenuated virulence in mice. We investigated the underlying mechanisms and found that loss of the transporters and altered phosphate availability influences the cell wall and membrane composition. These changes contribute to the shedding of capsule polysaccharide thus explaining the reduced size of capsules on mutants lacking the phosphate transporters. We also found an influence of the calcineurin pathway including calcium sensitivity and an involvement of the endoplasmic reticulum in the response to phosphate limitation. Furthermore, we identified membrane and lipid composition changes consistent with the role of phosphate in phospholipid biosynthesis and with previous studies implicating membrane integrity in caspofungin tolerance. Finally, we discovered a contribution of phosphate to titan cell formation, a cell type that displays modified cell wall and capsule composition. Overall, our analysis reinforces the importance of phosphate as a regulator of cell wall and membrane composition with implications for capsule attachment and antifungal drug susceptibility.
迫切需要新型抗真菌药物来治疗侵袭性真菌疾病。不幸的是，对其他重要真菌病原体具有杀菌作用的棘白菌素类药物对 无效， 是免疫功能低下人群中危及生命的脑膜脑炎的病原体。与钙调神经磷酸酶信号传导、细胞壁和膜组成相关的棘白菌素耐受性的促成机制正在出现。在此背景下，我们发现磷酸盐摄取缺陷会损害 对棘白菌素卡泊芬净的耐受性。我们之前对缺乏三种高亲和力磷酸盐转运蛋白的突变体的分析表明，多糖荚膜的形成减少，并且在小鼠中的毒力减弱。我们研究了潜在机制，发现转运蛋白的缺失和磷酸盐可用性的改变会影响细胞壁和膜的组成。这些变化导致荚膜多糖的脱落，从而解释了缺乏磷酸盐转运蛋白的突变体上荚膜尺寸减小的原因。我们还发现了钙调神经磷酸酶途径的影响，包括钙敏感性以及内质网参与对磷酸盐限制的反应。此外，我们确定了膜和脂质组成的变化，这与磷酸盐在磷脂生物合成中的作用以及先前关于膜完整性与卡泊芬净耐受性相关的研究一致。最后，我们发现磷酸盐对巨细胞形成有贡献，巨细胞是一种显示出修饰的细胞壁和荚膜组成的细胞类型。总体而言，我们的分析强化了磷酸盐作为细胞壁和膜组成调节剂的重要性，这对荚膜附着和抗真菌药物敏感性具有影响。
