Physiologically Relevant Alternative Carbon Sources Modulate Biofilm Formation, Cell Wall Architecture, and the Stress and Antifungal Resistance of Candida glabrata

Chew, Shu Yih; Ho, Ken; Cheah, Yoke Kqueen; Sandai, Doblin; Brown, Alistair J. P.; Than, Leslie Thian Lung

doi:10.3390/ijms20133172

Cited by 37 publications

(25 citation statements)

References 53 publications

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“…These cell wall-remodeled C. albicans cells become resistant to amphotericin B (AMB) and caspofungin (Ene et al, 2012). Similar results were demonstrated for C. glabrata strains that grown under an alternative carbon microenvironment showed altered cell wall architecture with a lower content of chitin and β-glucan, and with an increased outer mannan layer (Chew et al, 2019). These C. glabrata cells were also resistant to AMB when grown in lactate or oleate (Chew et al, 2019).…”

Section: Fungal Cell Wall Modifications and Antifungal Resistancesupporting

confidence: 77%

Fungal Cell Wall: Emerging Antifungals and Drug Resistance

Lima¹,

Colombo²,

Almeida³

2019

Front. Microbiol.

152

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The cell wall is an essential component in fungal homeostasis. The lack of a covering wall in human cells makes this component an attractive target for antifungal development. The host environment and antifungal stress can lead to cell wall modifications related to drug resistance. Antifungals targeting the cell wall including the new β-D-glucan synthase inhibitor ibrexafungerp and glycosyl-phosphatidyl Inositol (GPI) anchor pathway inhibitor fosmanogepix are promising weapons against antifungal resistance. The fosmanogepix shows strong in vitro activity against the multidrug-resistant species Candida auris, Fusarium solani, and Lomentospora prolificans. The alternative carbon sources in the infection site change the cell wall β-D-glucan and chitin composition, leading to echinocandin and amphotericin resistance. Candida populations that survive echinocandin exposure develop tolerance and show high chitin content in the cell wall, while fungal species such as Aspergillus flavus with a higher β-D-glucan content may show amphotericin resistance. Therefore understanding fungal cell dynamics has become important not only for host-fungal interactions, but also treatment of fungal infections. This review summarizes recent findings regarding antifungal therapy and development of resistance related to the fungal cell wall of the most relevant human pathogenic species.

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Section: Fungal Cell Wall Modifications and Antifungal Resistancesupporting

confidence: 77%

Fungal Cell Wall: Emerging Antifungals and Drug Resistance

Lima¹,

Colombo²,

Almeida³

2019

Front. Microbiol.

152

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“…Gluconeogenic genes are also induced in vivo (21,57), and these transcriptional changes are often advantageous for microbial pathogens. Stress resistance induced in the presence of alternative carbon sources has been observed in other Candida species, including C. glabrata and the emerging pathogen C. auris (58,59), and numerous examples of beneficial effects of utilization of alternative carbon sources have been seen in bacterial pathogens. For example, Staphylococcus aureus, a facultative intracellular pathogen, alters its central carbon metabolism to promote its survival in the phagosome (60,61).…”

Section: Discussionmentioning

confidence: 99%

Multiple Alternative Carbon Pathways Combine To Promote Candida albicans Stress Resistance, Immune Interactions, and Virulence

Williams

Lorenz

2020

mBio

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The phagocytic cells of the innate immune system are an essential first line of antimicrobial defense, and yet Candida albicans, one of the most problematic fungal pathogens, is capable of resisting the stresses imposed by the macrophage phagosome, eventually resulting in the destruction of the phagocyte. C. albicans rapidly adapts to the phagosome by upregulating multiple alternative carbon utilization pathways, particularly those for amino acids, carboxylic acids, and N-acetylglucosamine (GlcNAc). Here, we report that C. albicans recognizes these carbon sources both as crucial nutrients and as independent signals in its environment. Even in the presence of glucose, each carbon source promotes increased resistance to a unique profile of stressors; lactate promotes increased resistance to osmotic and cell wall stresses, amino acids increased resistance to oxidative and nitrosative stresses, and GlcNAc increased resistance to oxidative stress and caspofungin, while all three alternative carbon sources have been shown to induce resistance to fluconazole. Moreover, we show mutants incapable of utilizing these carbon sources, in particular, strains engineered to be defective in all three pathways, are significantly attenuated in both macrophage and mouse models, with additive effects observed as multiple carbon pathways are eliminated, suggesting that C. albicans simultaneously utilizes multiple carbon sources within the macrophage phagosome and during disseminated candidiasis. Taking the data together, we propose that, in addition to providing energy to the pathogen within host environments, alternative carbon sources serve as niche-specific priming signals that allow C. albicans to recognize microenvironments within the host and to prepare for stresses associated with that niche, thus promoting host adaptation and virulence. IMPORTANCE Candida albicans is a fungal pathogen and a significant cause of morbidity and mortality, particularly in people with defects, sometimes minor ones, in innate immunity. The phagocytes of the innate immune system, particularly macrophages and neutrophils, generally restrict this organism to its normal commensal niches, but C. albicans shows a robust and multifaceted response to these cell types. Inside macrophages, a key component of this response is the activation of multiple pathways for the utilization of alternative carbon sources, particularly amino acids, carboxylic acids, and N-acetylglucosamine. These carbon sources are key sources of energy and biomass but also independently promote stress resistance, induce cell wall alterations, and affect C. albicans interactions with macrophages. Engineered strains incapable of utilizing these alternative carbon pathways are attenuated in infection models. These data suggest that C. albicans recognizes nutrient composition as an indicator of specific host environments and tailors its responses accordingly.

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“…For instance, the capability of carbon assimilation has been reduced significantly in comparison to S. cerevisiae . In fact, C. glabrata is unable to utilize many carbon sources such as galactose, maltose, lactose, sucrose and raffinose and mainly rely on glucose and trehalose [ 36 ], it has been shown to be able to utilize certain alternative carbon sources such as carboxylic acids, fatty acids and alcohols [ 13 ]. Furthermore, adaptation to these alternative carbon sources also induced physiological changes associated with pathogenicity of C. glabrata .…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, addition of acetic acid to glucose-grown C. glabrata renders the cells to be more sensitive to fluconazole treatment, and these cells are also more susceptible to phagocytosis killing by macrophages [ 12 ]. Previously, we have demonstrated that alternative carbon sources also induce physiological changes related to the pathogenicity of C. glabrata [ 13 ]. These include changes in planktonic and biofilm growth, cell wall architecture, oxidative stress resistance and antifungal susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic and proteomic profiling revealed reprogramming of carbon metabolism in acetate-grown human pathogen Candida glabrata

et al. 2021

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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.

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Physiologically Relevant Alternative Carbon Sources Modulate Biofilm Formation, Cell Wall Architecture, and the Stress and Antifungal Resistance of Candida glabrata

Cited by 37 publications

References 53 publications

Fungal Cell Wall: Emerging Antifungals and Drug Resistance

Fungal Cell Wall: Emerging Antifungals and Drug Resistance

Multiple Alternative Carbon Pathways Combine To Promote Candida albicans Stress Resistance, Immune Interactions, and Virulence

Transcriptomic and proteomic profiling revealed reprogramming of carbon metabolism in acetate-grown human pathogen Candida glabrata

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