Generational distribution of a Candida glabrata population: Resilient old cells prevail, while younger cells dominate in the vulnerable host

PLoS Pathogens

Erika P. Orner¹  Luz Alonso-Crisóstomo²  Maurizio Del Poeta³  Tejas Bouklas³  Kalie Smith³  Mansa A. Munshi⁴  Bettina C. Fries⁴  Gábor Balázsi⁴  Elizabeth Diago-Navarro⁵  Tamás Székely Jr.⁶ 

[1] Department of Biomedical Engineering, 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;Department of Medicine, Division of Infectious Diseases, Stony Brook University, Stony Brook, New York, United States of America;Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, United States of America;The Louis and Beatrice Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York, United States of America;Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain

关键词: Neutrophils;    Aging;    Cell walls;    Death rates;    Fungal pathogens;    Antimicrobial resistance;    Age distribution;    Urine;   

DOI  :  10.1371/journal.ppat.1006355

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY