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Fulltext The glyoxylate cycle and alternative carbon metabolism as metabolic adaptation strategies of Candida glabrata: perspectives from Candida albicans and Saccharomyces cerevisiae

Chew SY, Chee WJY, Than LTL

J Biomed Sci, 2019 Jul 13;26(1):52.
PMID: 31301737 DOI: 10.1186/s12929-019-0546-5

BACKGROUND: Carbon utilization and metabolism are fundamental to every living organism for cellular growth. For intracellular human fungal pathogens such as Candida glabrata, an effective metabolic adaptation strategy is often required for survival and pathogenesis. As one of the host defence strategies to combat invading pathogens, phagocytes such as macrophages constantly impose restrictions on pathogens' access to their preferred carbon source, glucose. Surprisingly, it has been reported that engulfed C. glabrata are able to survive in this harsh microenvironment, further suggesting alternative carbon metabolism as a potential strategy for this opportunistic fungal pathogen to persist in the host.
MAIN TEXT: In this review, we discuss alternative carbon metabolism as a metabolic adaptation strategy for the pathogenesis of C. glabrata. As the glyoxylate cycle is an important pathway in the utilization of alternative carbon sources, we also highlight the key metabolic enzymes in the glyoxylate cycle and its necessity for the pathogenesis of C. glabrata. Finally, we explore the transcriptional regulatory network of the glyoxylate cycle.
CONCLUSION: Considering evidence from Candida albicans and Saccharomyces cerevisiae, this review summarizes the current knowledge of the glyoxylate cycle as an alternative carbon metabolic pathway of C. glabrata.

Matched MeSH terms: Candida glabrata/metabolism*
Fulltext Transcriptomic and proteomic profiling revealed reprogramming of carbon metabolism in acetate-grown human pathogen Candida glabrata

Chew SY, Brown AJP, Lau BYC, Cheah YK, Ho KL, Sandai D, et al.

J Biomed Sci, 2021 Jan 02;28(1):1.
PMID: 33388061 DOI: 10.1186/s12929-020-00700-8

BACKGROUND: Emergence of Candida glabrata, which causes potential life-threatening invasive candidiasis, has been widely associated with high morbidity and mortality. In order to cause disease in vivo, a robust and highly efficient metabolic adaptation is crucial for the survival of this fungal pathogen in human host. In fact, reprogramming of the carbon metabolism is believed to be indispensable for phagocytosed C. glabrata within glucose deprivation condition during infection.
METHODS: In this study, the metabolic responses of C. glabrata under acetate growth condition was explored using high-throughput transcriptomic and proteomic approaches.
RESULTS: Collectively, a total of 1482 transcripts (26.96%) and 242 proteins (24.69%) were significantly up- or down-regulated. Both transcriptome and proteome data revealed that the regulation of alternative carbon metabolism in C. glabrata resembled other fungal pathogens such as Candida albicans and Cryptococcus neoformans, with up-regulation of many proteins and transcripts from the glyoxylate cycle and gluconeogenesis, namely isocitrate lyase (ICL1), malate synthase (MLS1), phosphoenolpyruvate carboxykinase (PCK1) and fructose 1,6-biphosphatase (FBP1). In the absence of glucose, C. glabrata shifted its metabolism from glucose catabolism to anabolism of glucose intermediates from the available carbon source. This observation essentially suggests that the glyoxylate cycle and gluconeogenesis are potentially critical for the survival of phagocytosed C. glabrata within the glucose-deficient macrophages.
CONCLUSION: Here, we presented the first global metabolic responses of C. glabrata to alternative carbon source using transcriptomic and proteomic approaches. These findings implicated that reprogramming of the alternative carbon metabolism during glucose deprivation could enhance the survival and persistence of C. glabrata within the host.

Matched MeSH terms: Candida glabrata/metabolism*
Fulltext Physiologically Relevant Alternative Carbon Sources Modulate Biofilm Formation, Cell Wall Architecture, and the Stress and Antifungal Resistance of Candida glabrata

Chew SY, Ho KL, Cheah YK, Sandai D, Brown AJP, Than LTL

Int J Mol Sci, 2019 Jun 28;20(13).
PMID: 31261727 DOI: 10.3390/ijms20133172

Flexibility in carbon metabolism is pivotal for the survival and propagation of many human fungal pathogens within host niches. Indeed, flexible carbon assimilation enhances pathogenicity and affects the immunogenicity of Candida albicans. Over the last decade, Candida glabrata has emerged as one of the most common and problematic causes of invasive candidiasis. Despite this, the links between carbon metabolism, fitness, and pathogenicity in C. glabrata are largely unexplored. Therefore, this study has investigated the impact of alternative carbon metabolism on the fitness and pathogenic attributes of C. glabrata. We confirm our previous observation that growth on carbon sources other than glucose, namely acetate, lactate, ethanol, or oleate, attenuates both the planktonic and biofilm growth of C. glabrata, but that biofilms are not significantly affected by growth on glycerol. We extend this by showing that C. glabrata cells grown on these alternative carbon sources undergo cell wall remodeling, which reduces the thickness of their β-glucan and chitin inner layer while increasing their outer mannan layer. Furthermore, alternative carbon sources modulated the oxidative stress resistance of C. glabrata as well as the resistance of C. glabrata to an antifungal drug. In short, key fitness and pathogenic attributes of C. glabrata are shown to be dependent on carbon source. This reaffirms the perspective that the nature of the carbon sources available within specific host niches is crucial for C. glabrata pathogenicity during infection.

Matched MeSH terms: Candida glabrata/metabolism*
Fulltext Glyoxylate cycle gene ICL1 is essential for the metabolic flexibility and virulence of Candida glabrata

Chew SY, Ho KL, Cheah YK, Ng TS, Sandai D, Brown AJP, et al.

Sci Rep, 2019 02 26;9(1):2843.
PMID: 30808979 DOI: 10.1038/s41598-019-39117-1

The human fungal pathogen Candida glabrata appears to utilise unique stealth, evasion and persistence strategies in subverting the onslaught of host immune response during systemic infection. However, macrophages actively deprive the intracellular fungal pathogen of glucose, and therefore alternative carbon sources probably support the growth and survival of engulfed C. glabrata. The present study aimed to investigate the role of the glyoxylate cycle gene ICL1 in alternative carbon utilisation and its importance for the virulence of C. glabrata. The data showed that disruption of ICL1 rendered C. glabrata unable to utilise acetate, ethanol or oleic acid. In addition, C. glabrata icl1∆ cells displayed significantly reduced biofilm growth in the presence of several alternative carbon sources. It was also found that ICL1 is crucial for the survival of C. glabrata in response to macrophage engulfment. Disruption of ICL1 also conferred a severe attenuation in the virulence of C. glabrata in the mouse model of invasive candidiasis. In conclusion, a functional glyoxylate cycle is essential for C. glabrata to utilise certain alternative carbon sources in vitro and to display full virulence in vivo. This reinforces the view that antifungal drugs that target fungal Icl1 have potential for future therapeutic intervention.

Matched MeSH terms: Candida glabrata/metabolism