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

Date Published: May 10, 2017

Publisher: Public Library of Science

Author(s): Tejas Bouklas, Luz Alonso-Crisóstomo, Tamás Székely, Elizabeth Diago-Navarro, Erika P. Orner, Kalie Smith, Mansa A. Munshi, Maurizio Del Poeta, Gábor Balázsi, Bettina C. Fries, Leah E. Cowen.


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.

Partial Text

Candida glabrata infections are common in immunocompromised patients and associated with prolonged treatment [1, 2], extended length of hospital stay, high costs and high mortality rates [3, 4]. Over the last decade, the incidence of C. glabrata infections has increased considerably due to higher numbers of immunocompromised patients, as well as broad empiric antifungal prophylaxis, which promotes colonization with azole-resistant C. glabrata [1]. C. glabrata is a very successful human pathogen because it has a high intrinsic stress tolerance, enabling it to withstand oxidative stress [5]. The yeast disseminates and attaches to host cells and indwelling devices, where it forms biofilms [6]. In vitro phagocytosed C. glabrata cells are able to survive and replicate inside human and murine macrophages [7, 8]. Imaging studies demonstrate that primary human neutrophils can kill or release phagocytosed C. glabrata [9]. Consequently, neutropenia constitutes a major risk factor for disseminated candidiasis in colonized patients [10, 11].

To our knowledge, this is the first study to investigate replicative aging in clinical C. glabrata populations. Our data link replicative aging to pathogenesis in this important fungal pathogen. Specifically, we demonstrate that the natural process of aging results in a remodeling of the fungal cell wall leading to enhanced resilience. Furthermore, we show that neutrophil-mediated killing comprises the host’s selection pressure, which shifts the generational distribution of a C. glabrata population in vivo. Thus, this study supports a conceptually novel understanding of pathogenesis, where replicative aging in a yeast population facilitates demographic changes in the presence of a selective host response. Hence, the natural process of replication can be exploited as a unique mechanism of adaptation that contributes to phenotypic variation, resilience, and virulence. Since the phenotype of aging is not genetically inherited, but only seen through shifting selection pressures that promote persistence of older cells, the high risk of random permanent mutations is avoided. Instead constant rejuvenation through budding provides an assurance that all adaptive changes can be rapidly reversed as the daughter inherits asymmetrically [52, 53] and allows the emergence of a new generation.




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