Elsevier

Current Opinion in Microbiology

Volume 52, December 2019, Pages 27-34
Current Opinion in Microbiology

Regulatory mechanisms controlling morphology and pathogenesis in Candida albicans

https://doi.org/10.1016/j.mib.2019.04.005Get rights and content

Highlights

  • There is a strong association between C. albicans morphology and virulence.

  • C. albicans morphology control mechanisms may serve as important antifungal targets.

  • Several new global transcriptional mechanisms regulate C. albicans morphology.

  • C. albicans morphology is controlled by 5′ UTR-mediated translational mechanisms.

  • Several key biosynthesis pathways also function to regulate C. albicans morphology.

Candida albicans, a major human fungal pathogen, can cause a wide variety of both mucosal and systemic infections, particularly in immunocompromised individuals. Multiple lines of evidence suggest a strong association between virulence and the ability of C. albicans to undergo a reversible morphological transition from yeast to filamentous cells in response to host environmental cues. Most previous studies on mechanisms important for controlling the C. albicans morphological transition have focused on signaling pathways and sequence-specific transcription factors. However, in recent years a variety of novel mechanisms have been reported, including those involving global transcriptional regulation and translational control. A large-scale functional genomics screen has also revealed new roles in filamentation for certain key biosynthesis pathways. This review article will highlight several of these exciting recent discoveries and discuss how they are relevant to the development of novel antifungal strategies. Ultimately, components of mechanisms that control C. albicans morphogenesis and pathogenicity could potentially serve as viable antifungal targets.

Introduction

Candida albicans is a major human fungal pathogen and a leading cause of hospital-acquired bloodstream infections in the U.S, with an attributable mortality rate of 35–60% [1,2]. C. albicans is also responsible for a wide variety of mucosal infections, including oral and vaginal thrush [3, 4, 5, 6]. Immunocompromised individuals, including organ transplant recipients, HIV/AIDS patients and cancer patients are especially vulnerable to infections [5, 6, 7]. HIV/AIDS patients are particularly susceptible to mucosal infections whereas cancer patients and organ transplant recipients are susceptible to both mucosal and systemic infections [8, 9, 10, 11, 12, 13].

The ability of C. albicans to undergo a reversible morphological transition from yeast (single oval cells) to filaments (elongated cells attached end-to-end) is promoted in response to a variety of host environmental conditions and has long been associated with virulence and pathogenesis [14, 15, 16, 17]. Indeed, C. albicans filaments are known to play an important role in the establishment of biofilms, invasion of epithelial cell layers, breaching of endothelial cells and macrophages, tissue invasion, as well as contact sensing (thigmotropism) [17, 18, 19]. Initial studies showed that strains locked in either the yeast or filamentous form were highly attenuated for virulence in a mouse model of systemic candidiasis [20, 21, 22]. More definitive evidence came from a subsequent study which demonstrated that allowing a genetically engineered strain to transition from yeast to filaments at different time points during the course of an infection was sufficient to promote virulence [23]. A complementary experiment showed that inoculating mice with yeast cells of a strain that has been engineered to rapidly undergo the yeast-filament transition and promote strong hyphal growth was sufficient to enhance virulence in a mouse model of systemic candidiasis [24]. Additional evidence supporting a strong association between filamentation and pathogenesis came from the demonstration that a C. albicans strain deleted for HGC1, encoding a cyclin-related protein specifically important for hyphal growth, was highly attenuated for virulence in the mouse systemic model [25]. Finally, a recent large-scale functional genomics screen has indicated that most C. albicans mutants defective for filamentation are also defective for virulence [26••]. Interestingly, however, this study also showed that filamentation is not required for macrophage lysis and an independent genetic study has identified C. albicans mutants that are defective for kidney infectivity but not morphogenesis [26••,27]. While these studies suggest that the relationship between morphology and virulence in C. albicans may be more complex than expected, the large majority of evidence indicates a strong association between the yeast-filament transition and pathogenesis. Also consistent with this notion, several small molecule compounds have recently been identified that strongly inhibit C. albicans filamentation and biofilm formation as well as virulence and pathogenicity [28,29,30••]. These findings are important because they suggest that targeting mechanisms that promote the C. albicans yeast-filament transition may serve as a viable strategy for the development of novel and more effective classes of antifungals [31]. Over the past several years, many new and exciting advances have been made in identifying and characterizing such mechanisms. This review article will serve to highlight several recently discovered global transcriptional and translational mechanisms important for the C. albicans yeast-filament transition as well as certain previously known biosynthesis pathways that have been shown to play novel roles in this process. New insights and perspectives into whether components of these mechanisms and pathways may serve as promising targets for novel antifungals will also be provided.

Section snippets

Global transcriptional mechanisms that control the C. albicans morphological transition

A variety of transcription factors have been shown to regulate the C. albicans yeast-filament transition [32,33]. Whole-genome transcriptional profiling experiments have demonstrated that these factors generally control large sets of target genes, several of which encode components of the C. albicans filamentous growth program [34, 35, 36]. While most of these transcription factors are promoter-specific DNA-binding proteins, considerably less is known about the role of general transcription

Regulation of C. albicans morphogenesis and pathogenicity by translational mechanisms

While a variety of transcriptional mechanisms have been shown to regulate the C. albicans yeast-filament transition, until recently very little, if anything, was known about translational control of this process. An initial study indicated that UME6, a key transcriptional regulator of morphology and virulence, is translationally regulated by an exceptionally long (>3 kb) 5′ untranslated region (UTR) [35,55••]. The 5′ UTR was specifically shown to inhibit translational efficiency of UME6 and

Functional genomics identifies biosynthesis pathways with new roles in C. albicans filamentation

A recent large-scale functional genomics screen has provided an unbiased global approach to identify factors that play an important role in C. albicans morphogenesis [26••]. In addition to identifying many previously known regulators of filamentation, this screen also identified two biosynthesis pathways that were found to play unexpected roles in the C. albicans yeast-filament transition. The first is the ergosterol biosynthesis pathway, which already represents a known target for the azole

Conclusions and perspectives

Because the C. albicans yeast-filament transition is strongly associated with virulence and pathogenicity, many studies have focused on mechanisms that control this transition. In general, post-translational mechanisms that are mediated by signaling pathways as well as transcriptional mechanisms that work through sequence-specific DNA-binding protein transcription factors have received the greatest attention. This review serves to highlight several recently discovered alternative mechanisms,

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The author would like to thank Brian Wickes for critical reading of the manuscript and useful suggestions. Funding: this work was supported by the National Institutes of Health [grant numbers R01AI127692, R21AI130668, R21AI129883]. The content is solely the responsibility of the author and does not necessarily reflect the official views of the National Institutes of Health or the National Institute of Allergy and Infectious Diseases.

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