ABSTRACT

Candida glabrata is a prominent pathogenic yeast which exhibits a unique ability to survive the harsh environment of host immune cells. In this study, we describe the role of the transcription factor encoded by the gene CAGL0F09229g, here named CgTog1 after its Saccharomyces cerevisiae ortholog, as a new determinant of C. glabrata virulence. Interestingly, Tog1 is absent in the other clinically relevant Candida species (C. albicans, C. parapsilosis, C. tropicalis, C. auris), being exclusive to C. glabrata. CgTog1 was found to be required for oxidative stress resistance and for the modulation of reactive oxygen species inside C. glabrata cells. Also, CgTog1 was observed to be a nuclear protein, whose activity up-regulates the expression of 147 genes and represses 112 genes in C. glabrata cells exposed to H₂O₂, as revealed through RNA-seq-based transcriptomics analysis. Given the importance of oxidative stress response in the resistance to host immune cells, the effect of CgTOG1 expression in yeast survival upon phagocytosis by Galleria mellonella hemocytes was evaluated, leading to the identification of CgTog1 as a determinant of yeast survival upon phagocytosis. Interestingly, CgTog1 targets include many whose expression changes in C. glabrata cells after engulfment by macrophages, including those involved in reprogrammed carbon metabolism, glyoxylate cycle and fatty acid degradation. In summary, CgTog1 is a new and specific regulator of virulence in C. glabrata, contributing to oxidative stress resistance and survival upon phagocytosis by host immune cells.

摘要

光滑念珠菌是一种突出的致病酵母，具有在宿主免疫细胞的恶劣环境中生存的独特能力。在这项研究中，我们描述了由基因CAGL0F09229g编码的转录因子的作用，这里以其酿酒酵母直系同源物命名为 CgTog1 ，作为C. glabrata毒力的新决定因素。有趣的是，Tog1 在其他临床相关的念珠菌属物种（白色念珠菌、近平滑念珠菌、热带念珠菌、耳念珠菌）中不存在，是光滑念珠菌独有的。发现 CgTog1 是抗氧化应激和调节C. glabrata内活性氧物种所必需的细胞。此外，通过基于 RNA序列的转录组学分析显示，CgTog1 被观察到是一种核蛋白，其活性上调了 147 个基因的表达并抑制了暴露于 H ₂ O _{2 的}光滑光球藻细胞中的112 个基因。鉴于氧化应激反应在宿主免疫细胞抗性中的重要性，评估了酵母存活中CgTOG1表达对大蜡螟血细胞吞噬作用的影响，从而将 CgTog1 鉴定为吞噬作用后酵母存活的决定因素。有趣的是，CgTog1 目标包括许多在C. glabrata 中表达变化的目标被巨噬细胞吞噬后的细胞，包括那些参与重新编程的碳代谢、乙醛酸循环和脂肪酸降解的细胞。总之，CgTog1 是一种新的特异性C. glabrata毒力调节剂，有助于抗氧化应激和宿主免疫细胞吞噬作用后的存活。