Bouklas Tejas, Alonso-Crisóstomo Luz, Székely Tamás, Diago-Navarro Elizabeth, Orner Erika P, Smith Kalie, Munshi Mansa A, Del Poeta Maurizio, Balázsi Gábor, Fries Bettina C
Department of Medicine, Division of Infectious Diseases, Stony Brook University, Stony Brook, New York, United States of America.
Department of Biomedical Sciences, Long Island University-Post, Brookville, New York, United States of America.
PLoS Pathog. 2017 May 10;13(5):e1006355. doi: 10.1371/journal.ppat.1006355. eCollection 2017 May.
Similar to other yeasts, the human pathogen Candida glabrata ages when it undergoes asymmetric, finite cell divisions, which determines its replicative lifespan. We sought to investigate if and how aging changes resilience of C. glabrata populations in the host environment. Our data demonstrate that old C. glabrata are more resistant to hydrogen peroxide and neutrophil killing, whereas young cells adhere better to epithelial cell layers. Consequently, virulence of old compared to younger C. glabrata cells is enhanced in the Galleria mellonella infection model. Electron microscopy images of old C. glabrata cells indicate a marked increase in cell wall thickness. Comparison of transcriptomes of old and young C. glabrata cells reveals differential regulation of ergosterol and Hog pathway associated genes as well as adhesion proteins, and suggests that aging is accompanied by remodeling of the fungal cell wall. Biochemical analysis supports this conclusion as older cells exhibit a qualitatively different lipid composition, leading to the observed increased emergence of fluconazole resistance when grown in the presence of fluconazole selection pressure. Older C. glabrata cells accumulate during murine and human infection, which is statistically unlikely without very strong selection. Therefore, we tested the hypothesis that neutrophils constitute the predominant selection pressure in vivo. When we altered experimentally the selection pressure by antibody-mediated removal of neutrophils, we observed a significantly younger pathogen population in mice. Mathematical modeling confirmed that differential selection of older cells is sufficient to cause the observed demographic shift in the fungal population. Hence our data support the concept that pathogenesis is affected by the generational age distribution of the infecting C. glabrata population in a host. We conclude that replicative aging constitutes an emerging trait, which is selected by the host and may even play an unanticipated role in the transition from a commensal to a pathogen state.
与其他酵母类似，人类病原体光滑念珠菌在经历不对称的有限细胞分裂时会老化，这决定了其复制寿命。我们试图研究老化是否以及如何改变光滑念珠菌群体在宿主环境中的恢复力。我们的数据表明，老化的光滑念珠菌对过氧化氢和中性粒细胞杀伤更具抵抗力，而年轻细胞则更能较好地黏附于上皮细胞层。因此，在大蜡螟感染模型中，与年轻的光滑念珠菌细胞相比，老化细胞的毒力增强。老化的光滑念珠菌细胞的电子显微镜图像显示细胞壁厚度显著增加。对老化和年轻的光滑念珠菌细胞转录组的比较揭示了麦角固醇和Hog途径相关基因以及黏附蛋白的差异调节，并表明老化伴随着真菌细胞壁的重塑。生化分析支持这一结论，因为老化细胞表现出质上不同的脂质组成,导致在氟康唑选择压力下生长时观察到的氟康唑耐药性出现增加。在小鼠和人类感染过程中，老化的光滑念珠菌细胞会积累，若无非常强的选择作用,从统计学角度来看这是不太可能的。因此，我们测试了中性粒细胞在体内构成主要选择压力这一假设。当我们通过抗体介导去除中性粒细胞来实验性改变选择压力时，我们在小鼠中观察到病原体群体明显更年轻。数学模型证实，对老化细胞的差异选择足以导致观察到的真菌群体的人口统计学变化。因此,我们的数据支持这样一种概念,即发病机制受宿主中感染的光滑念珠菌群体的代龄分布影响。我们得出结论，复制性老化构成一种新出现的特征，它由宿主选择,甚至可能在从共生状态向致病状态的转变中发挥意想不到的作用。
