Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany.
Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany.
PLoS Pathog. 2021 Oct 28;17(10):e1010037. doi: 10.1371/journal.ppat.1010037. eCollection 2021 Oct.
The opportunistic pathogen Candida glabrata is the second most frequent causative agent of vulvovaginal candidiasis (VVC), a disease that affects 70-75% of women at least once during their life. However, C. glabrata is almost avirulent in mice and normally incapable of inflicting damage to vaginal epithelial cells in vitro. We thus proposed that host factors present in vivo may influence C. glabrata pathogenicity. We, therefore, analyzed the impact of albumin, one of the most abundant proteins of the vaginal fluid. The presence of human, but not murine, albumin dramatically increased the potential of C. glabrata to damage vaginal epithelial cells. This effect depended on macropinocytosis-mediated epithelial uptake of albumin and subsequent proteolytic processing. The enhanced pathogenicity of C. glabrata can be explained by a combination of beneficial effects for the fungus, which includes an increased access to iron, accelerated growth, and increased adhesion. Screening of C. glabrata deletion mutants revealed that Hap5, a key regulator of iron homeostasis, is essential for the albumin-augmented damage potential. The albumin-augmented pathogenicity was reversed by the addition of iron chelators and a similar increase in pathogenicity was shown by increasing the iron availability, confirming a key role of iron. Accelerated growth not only led to higher cell numbers, but also to increased fungal metabolic activity and oxidative stress resistance. Finally, the albumin-driven enhanced damage potential was associated with the expression of distinct C. glabrata virulence genes. Transcriptional responses of the epithelial cells suggested an unfolded protein response (UPR) and ER-stress responses combined with glucose starvation induced by fast growing C. glabrata cells as potential mechanisms by which cytotoxicity is mediated.Collectively, we demonstrate that albumin augments the pathogenic potential of C. glabrata during interaction with vaginal epithelial cells. This suggests a role for albumin as a key player in the pathogenesis of VVC.
机会性病原体假丝酵母菌是引起外阴阴道念珠菌病（VVC）的第二大常见病原体，这种疾病影响了 70-75%的女性，她们一生中至少会患一次。然而，假丝酵母菌在小鼠中几乎没有毒性，通常不能在体外对阴道上皮细胞造成损伤。因此，我们假设体内存在的宿主因素可能会影响假丝酵母菌的致病性。因此，我们分析了白蛋白的影响，白蛋白是阴道液中最丰富的蛋白质之一。人白蛋白的存在而非鼠白蛋白的存在显著增加了假丝酵母菌损伤阴道上皮细胞的潜力。这种效应依赖于巨胞饮作用介导的上皮细胞对白蛋白的摄取以及随后的蛋白水解处理。假丝酵母菌致病性的增强可以通过真菌的有益作用来解释，包括增加对铁的获取、加速生长和增加粘附。对假丝酵母菌缺失突变体的筛选表明，Hap5 是铁平衡的关键调节剂，是白蛋白增强损伤潜力所必需的。添加铁螯合剂和增加铁的可用性可以逆转白蛋白增强的致病性，这证实了铁的关键作用。快速生长不仅导致细胞数量增加，而且还增加了真菌的代谢活性和抗氧化应激抗性。最后，白蛋白驱动的增强损伤潜力与特定的假丝酵母菌毒力基因的表达有关。上皮细胞的转录反应表明未折叠蛋白反应（UPR）和内质网应激反应与快速生长的假丝酵母菌细胞诱导的葡萄糖饥饿相结合，作为细胞毒性介导的潜在机制。总之，我们证明了白蛋白在与阴道上皮细胞相互作用时增强了假丝酵母菌的致病潜力。这表明白蛋白作为 VVC 发病机制中的关键因素之一发挥作用。
