Regulatory mechanisms controlling morphology and pathogenesis in Candida albicans
Graphical abstract
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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