scholarly journals Mucosal Bacteria Modulate Candida albicans Virulence in Oropharyngeal Candidiasis

mBio ◽  
2021 ◽  
Author(s):  
M. Bertolini ◽  
R. Vazquez Munoz ◽  
L. Archambault ◽  
S. Shah ◽  
J. G. S. Souza ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Carbon Source ◽  
Oral Infection ◽  
Infection Model ◽  
Oropharyngeal Candidiasis ◽  
Fungal Virulence ◽  
Bacterial Composition ◽  
Content Type ◽  
Host Environment ◽  
Bacterial Microbiome

By comparing Candida albicans virulence and the mucosal bacterial composition in a mouse oral infection model, we were able to dissect the effects of the host environment (immunosuppression), infection with C. albicans , and local modulating factors (availability of sucrose as a carbon source) on the mucosal bacterial microbiome and its role on fungal virulence. We showed that changes in endogenous microbial communities in response to sucrose can lead to attenuation of fungal disease.

scholarly journals Metabolic Reprogramming in the Opportunistic Yeast Candida albicans in Response to Hypoxia

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Anaïs Burgain ◽  
Faiza Tebbji ◽  
Inès Khemiri ◽  
Adnane Sellam
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Metabolic Pathways ◽  
Membrane Lipids ◽  
Oxygen Depletion ◽  
Metabolic Reprogramming ◽  
Pathogenic Yeast ◽  
Fungal Virulence ◽  
Content Type ◽  
The Impact

ABSTRACT Hypoxia is the predominant condition that the human opportunistic fungus Candida albicans encounters in the majority of the colonized niches within the host. So far, the impact of such a condition on the overall metabolism of this important human-pathogenic yeast has not been investigated. Here, we have undertaken a time-resolved metabolomics analysis to uncover the metabolic landscape of fungal cells experiencing hypoxia. Our data showed a dynamic reprogramming of many fundamental metabolic pathways, such as glycolysis, the pentose phosphate pathway, and different metabolic routes related to fungal cell wall biogenesis. The C. albicans lipidome was highly affected by oxygen depletion, with an increased level of free fatty acids and biochemical intermediates of membrane lipids, including phospholipids, lysophospholipids, sphingolipids, and mevalonate. The depletion of oxygen-dependent lipids such as ergosterol or phosphatidylcholine with longer and polyunsaturated lateral fatty acid chains was observed only at the later hypoxic time point (180 min). Transcriptomics data supported the main metabolic response to hypoxia when matched to our metabolomic profiles. The hypoxic metabolome reflected different physiological alterations of the cell wall and plasma membrane of C. albicans under an oxygen-limiting environment that were confirmed by different approaches. This study provided a framework for future in vivo investigations to examine relevant hypoxic metabolic trajectories in fungal virulence and fitness within the host. IMPORTANCE A critical aspect of cell fitness is the ability to sense and adapt to variations in oxygen levels in their local environment. Candida albicans is an opportunistic yeast that is the most prevalent human fungal pathogen. While hypoxia is the predominant condition that C. albicans encounters in most of its niches, its impact on fungal metabolism remains unexplored so far. Here, we provided a detailed landscape of the C. albicans metabolome that emphasized the importance of many metabolic routes for the adaptation of this yeast to oxygen depletion. The fungal hypoxic metabolome identified in this work provides a framework for future investigations to assess the contribution of relevant metabolic pathways in the fitness of C. albicans and other human eukaryotic pathogens with similar colonized human niches. As hypoxia is present at most of the fungal infection foci in the host, hypoxic metabolic pathways are thus an attractive target for antifungal therapy.

scholarly journals Three Related Enzymes in Candida albicans Achieve Arginine- and Agmatine-Dependent Metabolism That Is Essential for Growth and Fungal Virulence

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Katja Schaefer ◽  
Jeanette Wagener ◽  
Ryan M. Ames ◽  
Stella Christou ◽  
Donna M. MacCallum ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amino Acid ◽  
Galleria Mellonella ◽  
Fungal Growth ◽  
Open Reading Frames ◽  
Mammalian Host ◽  
No Production ◽  
Triple Mutant ◽  
Fungal Virulence ◽  
Content Type

ABSTRACT Amino acid metabolism is crucial for fungal growth and development. Ureohydrolases produce amines when acting on l-arginine, agmatine, and guanidinobutyrate (GB), and these enzymes generate ornithine (by arginase), putrescine (by agmatinase), or GABA (by 4-guanidinobutyrase or GBase). Candida albicans can metabolize and grow on arginine, agmatine, or guanidinobutyrate as the sole nitrogen source. Three related C. albicans genes whose sequences suggested that they were putative arginase or arginase-like genes were examined for their role in these metabolic pathways. Of these, Car1 encoded the only bona fide arginase, whereas we provide evidence that the other two open reading frames, orf19.5862 and orf19.3418, encode agmatinase and guanidinobutyrase (Gbase), respectively. Analysis of strains with single and multiple mutations suggested the presence of arginase-dependent and arginase-independent routes for polyamine production. CAR1 played a role in hyphal morphogenesis in response to arginine, and the virulence of a triple mutant was reduced in both Galleria mellonella and Mus musculus infection models. In the bloodstream, arginine is an essential amino acid that is required by phagocytes to synthesize nitric oxide (NO). However, none of the single or multiple mutants affected host NO production, suggesting that they did not influence the oxidative burst of phagocytes. IMPORTANCE We show that the C. albicans ureohydrolases arginase (Car1), agmatinase (Agt1), and guanidinobutyrase (Gbu1) can orchestrate an arginase-independent route for polyamine production and that this is important for C. albicans growth and survival in microenvironments of the mammalian host.

scholarly journals The F-Box Protein Fbp1 Regulates Sexual Reproduction and Virulence in Cryptococcus neoformans

2011 ◽  
Vol 10 (6) ◽  
pp. 791-802 ◽  
Author(s):  
Tong-Bao Liu ◽  
Yina Wang ◽  
Sabriya Stukes ◽  
Qing Chen ◽  
Arturo Casadevall ◽  
...  
Keyword(s):  
Sexual Reproduction ◽  
Cryptococcus Neoformans ◽  
Stress Responses ◽  
Membrane Integrity ◽  
Infection Model ◽  
Calcofluor White ◽  
Fungal Virulence ◽  
Content Type ◽  
F Box Protein

ABSTRACTCryptococcus neoformansis the leading cause of fungal meningitis in immunocomprised populations. Although extensive studies have been conducted on signal transduction pathways important for fungal sexual reproduction and virulence, how fungal virulence is regulated during infection is still not understood. In this study, we identified the F-box protein Fbp1, which contains a putative F-box domain and 12 leucine-rich repeats (LRR). Althoughfbp1mutants showed normal growth and produced normal major virulence factors, such as melanin and capsule, Fbp1 was found to be essential for fungal virulence, asfbp1mutants were avirulent in a murine systemic-infection model. Fbp1 is also important for fungal sexual reproduction. Basidiospore production was blocked in bilateral mating betweenfbp1mutants, even though normal dikaryotic hyphae were observed during mating.In vitroassays of stress responses revealed thatfbp1mutants are hypersensitive to SDS, but not calcofluor white (CFW) or Congo red, indicating that Fbp1 may regulate cell membrane integrity. Fbp1 physically interacts with Skp1 homologues in bothSaccharomyces cerevisiaeandC. neoformansvia its F-box domain, suggesting it may function as part of an SCF (Skp1, Cullins, F-box proteins) E3 ligase. Overall, our study revealed that the F-box protein Fbp1 is essential for fungal sporulation and virulence inC. neoformans, which likely represents a conserved novel virulence control mechanism that involves the SCF E3 ubiquitin ligase-mediated proteolysis pathway.

scholarly journals Dramatic Improvement of CRISPR/Cas9 Editing in Candida albicans by Increased Single Guide RNA Expression

mSphere ◽  
2017 ◽  
Vol 2 (2) ◽  
Author(s):  
Henry Ng ◽  
Neta Dean
Keyword(s):  
Candida Albicans ◽  
Genome Editing ◽  
Virulence Factors ◽  
Fungal Pathogen ◽  
Fungal Virulence ◽  
Important Conclusion ◽  
Content Type ◽  
Guide Rna ◽  
Improve Efficiency ◽  
Human Fungal Pathogen

ABSTRACT Candida albicans is an important human fungal pathogen. An understanding of fungal virulence factors has been slow because C. albicans is genetically intractable. The recent development of CRISPR/Cas in C. albicans (V. K. Vyas, M. I. Barrasa, G. R. Fink, Sci Adv 1:e1500248, 2015, https://doi.org/10.1126/sciadv.1500248 ) has the potential to circumvent this problem. However, as has been found in other organisms, CRISPR/Cas mutagenesis efficiency can be frustratingly variable. Here, we systematically examined parameters hypothesized to alter sgRNA intracellular levels in order to optimize CRISPR/Cas in C. albicans. Our most important conclusion is that increased sgRNA expression and maturation dramatically improve efficiency of CRISPR/Cas mutagenesis in C. albicans by ~10-fold. Thus, we anticipate that the modifications described here will further advance the application of CRISPR/Cas for genome editing in C. albicans. The clustered regularly interspaced short palindromic repeat system with CRISPR-associated protein 9 nuclease (CRISPR/Cas9) has emerged as a versatile tool for genome editing in Candida albicans. Mounting evidence from other model systems suggests that the intracellular levels of single guide RNA (sgRNA) limit the efficiency of Cas9-dependent DNA cleavage. Here, we tested this idea and describe a new means of sgRNA delivery that improves previously described methods by ~10-fold. The efficiency of Cas9/sgRNA-dependent cleavage and repair of a single-copy yeast enhanced monomeric red fluorescent protein (RFP) gene was measured as a function of various parameters that are hypothesized to affect sgRNA accumulation, including transcriptional and posttranscriptional processing. We analyzed different promoters (SNR52, ADH1, and tRNA), as well as different posttranscriptional RNA processing schemes that serve to generate or stabilize mature sgRNA with precise 5′ and 3′ ends. We compared the effects of flanking sgRNA with self-cleaving ribozymes or by tRNA, which is processed by endogenous RNases. These studies demonstrated that sgRNA flanked by a 5′ tRNA and transcribed by a strong RNA polymerase II ADH1 promoter increased Cas9-dependent RFP mutations by 10-fold. Examination of double-strand-break (DSB) repair in strains hemizygous for RFP demonstrated that both homology-directed and nonhomologous end-joining pathways were used to repair breaks. Together, these results support the model that gRNA expression can be rate limiting for efficient CRISPR/Cas mutagenesis in C. albicans. IMPORTANCE Candida albicans is an important human fungal pathogen. An understanding of fungal virulence factors has been slow because C. albicans is genetically intractable. The recent development of CRISPR/Cas in C. albicans (V. K. Vyas, M. I. Barrasa, G. R. Fink, Sci Adv 1:e1500248, 2015, https://doi.org/10.1126/sciadv.1500248 ) has the potential to circumvent this problem. However, as has been found in other organisms, CRISPR/Cas mutagenesis efficiency can be frustratingly variable. Here, we systematically examined parameters hypothesized to alter sgRNA intracellular levels in order to optimize CRISPR/Cas in C. albicans. Our most important conclusion is that increased sgRNA expression and maturation dramatically improve efficiency of CRISPR/Cas mutagenesis in C. albicans by ~10-fold. Thus, we anticipate that the modifications described here will further advance the application of CRISPR/Cas for genome editing in C. albicans.

scholarly journals Antifungal Activity of Mammalian Serum Amyloid A1 against Candida albicans

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Jiao Gong ◽  
Jun Wu ◽  
Melanie Ikeh ◽  
Li Tao ◽  
Yulong Zhang ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Membrane Integrity ◽  
Systemic Infection ◽  
Serum Amyloid ◽  
Infection Model ◽  
Fungal Cell ◽  
Content Type ◽  
Cell Membrane Integrity ◽  
Amyloid A

ABSTRACT Mammalian serum amyloid A (SAA) is a major acute phase protein that shows a massive increase in plasma concentration during inflammation. In the present study, we demonstrate that the expression of mouse SAA1 in serum was increased when infected with Candida albicans, a major human fungal pathogen, in a systemic infection model. We then set out to investigate the antifungal activity of SAA proteins against C. albicans. Recombinant human and mouse SAA1 (rhSAA1 and rmSAA1) were expressed and purified in Escherichia coli. Both rhSAA1 and rmSAA1 exhibited a potent antifungal activity against C. albicans. We further demonstrate that rhSAA1 binds to the cell surface of C. albicans, disrupts cell membrane integrity, and induces rapid fungal cell death in C. albicans. Our finding expands the known functions of SAA1 and provides new insight into host-Candida interactions during fungal infection.

scholarly journals The Heat-Induced Molecular Disaggregase Hsp104 of Candida albicans Plays a Role in Biofilm Formation and Pathogenicity in a Worm Infection Model

2012 ◽  
Vol 11 (8) ◽  
pp. 1012-1020 ◽  
Author(s):  
Alessandro Fiori ◽  
Soňa Kucharíková ◽  
Gilmer Govaert ◽  
Bruno P. A. Cammue ◽  
Karin Thevissen ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Stress Responses ◽  
Biofilm Formation ◽  
Fungal Pathogens ◽  
Elevated Temperatures ◽  
Structural Defects ◽  
Infection Model ◽  
Content Type

ABSTRACT The consequences of deprivation of the molecular chaperone Hsp104 in the fungal pathogen Candida albicans were investigated. Mutants lacking HSP104 became hypersusceptible to lethally high temperatures, similarly to the corresponding mutants of Saccharomyces cerevisiae , whereas normal susceptibility was restored upon reintroduction of the gene. By use of a strain whose only copy of HSP104 is an ectopic gene under the control of a tetracycline-regulated promoter, expression of Hsp104 prior to the administration of heat shock could be demonstrated to be sufficient to confer protection from the subsequent temperature increase. This result points to a key role for Hsp104 in orchestrating the cell response to elevated temperatures. Despite their not showing evident growth or morphological defects, biofilm formation by cells lacking HSP104 proved to be defective in two established in vitro models that use polystyrene and polyurethane as the substrates. Biofilms formed by the wild-type and HSP104 -reconstituted strains showed patterns of intertwined hyphae in the extracellular matrix. In contrast, biofilm formed by the hsp104 Δ/ hsp104 Δ mutant showed structural defects and appeared patchy and loose. Decreased virulence of the hsp104 Δ/ hsp104 Δ mutant was observed in the Caenorhabditis elegans infection model, in which high in vivo temperature does not play a role. In agreement with the view that stress responses in fungal pathogens may have evolved to provide niche-specific adaptation to environmental conditions, these results provide an indication of a temperature-independent role for Hsp104 in support of Candida albicans virulence, in addition to its key role in governing thermotolerance.

scholarly journals In Vivo Efficacy of Ellagic Acid against Candida albicans in a Drosophila melanogaster Infection Model

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Aline da Graça Sampaio ◽  
Aline Vidal Lacerda Gontijo ◽  
Helena Marcolla Araujo ◽  
Cristiane Yumi Koga-Ito
Keyword(s):  
Drosophila Melanogaster ◽  
Candida Albicans ◽  
Ellagic Acid ◽  
Antimicrobial Effect ◽  
Infection Model ◽  
Survival Curves ◽  
Content Type ◽  
Content Model ◽  
Promising Tool

ABSTRACT The aim of this study was to evaluate the antifungal activity and the toxicity of ellagic acid (EA) using a Drosophila melanogaster model. Candida albicans bacteria were inoculated into Toll heterozygous flies. Survival curves were obtained for the evaluation of the antimicrobial effect and toxicity of EA. A protective effect of EA against fungal infection in Drosophila melanogaster was observed at nontoxic concentrations. This study showed that EA is a promising tool for the treatment of candidiasis.

scholarly journals Candida albicans PEP12 Is Required for Biofilm Integrity and In Vivo Virulence

2009 ◽  
Vol 9 (2) ◽  
pp. 266-277 ◽  
Author(s):  
Suresh K. A. Palanisamy ◽  
Melissa A. Ramirez ◽  
Michael Lorenz ◽  
Samuel A. Lee
Keyword(s):  
Candida Albicans ◽  
Lipolytic Activity ◽  
Infection Model ◽  
Temperature Sensitive ◽  
Null Mutant ◽  
Macrophage Infection ◽  
Content Type ◽  
Vacuolar Acidification

ABSTRACT To investigate the role of the prevacuolar secretion pathway in biofilm formation and virulence in Candida albicans, we cloned and analyzed the C. albicans homolog of the Saccharomyces cerevisiae prevacuolar trafficking gene PEP12. C. albicans PEP12 encodes a deduced t-SNARE that is 28% identical to S. cerevisiae Pep12p, and plasmids bearing C. albicans PEP12 complemented the abnormal vacuolar morphology and temperature-sensitive growth of an S. cerevisiae pep12 null mutant. The C. albicans pep12 Δ null mutant was defective in endocytosis and vacuolar acidification and accumulated 40- to 60-nm cytoplasmic vesicles near the plasma membrane. Secretory defects included increased extracellular proteolytic activity and absent lipolytic activity. The pep12Δ null mutant was more sensitive to cell wall stresses and antifungal agents than the isogenic complemented strain or the control strain DAY185. Notably, the biofilm formed by the pep12Δ mutant was reduced in overall mass and fragmented completely upon the slightest disturbance. The pep12Δ mutant was markedly reduced in virulence in an in vitro macrophage infection model and an in vivo mouse model of disseminated candidiasis. These results suggest that C. albicans PEP12 plays a key role in biofilm integrity and in vivo virulence.

scholarly journals In VitroandIn VivoActivities of Pterostilbene against Candida albicans Biofilms

2014 ◽  
Vol 58 (4) ◽  
pp. 2344-2355 ◽  
Author(s):  
De-Dong Li ◽  
Lan-Xue Zhao ◽  
Eleftherios Mylonakis ◽  
Gan-Hai Hu ◽  
Yong Zou ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Growth Defect ◽  
Ergosterol Biosynthesis ◽  
Infection Model ◽  
Content Type ◽  
Camp Pathway

ABSTRACTPterostilbene (PTE) is a stilbene-derived phytoalexin that originates from several natural plant sources. In this study, we evaluated the activity of PTE againstCandida albicansbiofilms and explored the underlying mechanisms. In 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assays, biofilm biomass measurement, confocal laser scanning microscopy, and scanning electron microscopy, we found that ≤16 μg/ml PTE had a significant effect againstC. albicansbiofilmsin vitro, while it had no fungicidal effect on planktonicC. albicanscells, which suggested a unique antibiofilm effect of PTE. Then we found that PTE could inhibit biofilm formation and destroy the maintenance of mature biofilms. At 4 μg/ml, PTE decreased cellular surface hydrophobicity (CSH) and suppressed hyphal formation. Gene expression microarrays and real-time reverse transcription-PCR showed that exposure ofC. albicansto 16 μg/ml PTE altered the expression of genes that function in morphological transition, ergosterol biosynthesis, oxidoreductase activity, and cell surface and protein unfolding processes (heat shock proteins). Filamentation-related genes, especially those regulated by the Ras/cyclic AMP (cAMP) pathway, includingECE1,ALS3,HWP1,HGC1, andRAS1itself, were downregulated upon PTE treatment, indicating that the antibiofilm effect of PTE was related to the Ras/cAMP pathway. Then, we found that the addition of exogenous cAMP reverted the PTE-induced filamentous growth defect. Finally, with a rat central venous catheter infection model, we confirmed thein vivoactivity of PTE againstC. albicansbiofilms. Collectively, PTE had strong activities againstC. albicansbiofilms bothin vitroandin vivo, and these activities were associated with the Ras/cAMP pathway.

scholarly journals mSphere of Influence: Decoding Transcriptional Regulatory Networks To Illuminate the Mechanisms of Microbial Pathogenicity

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Sadri Znaidi
Keyword(s):  
Candida Albicans ◽  
Functional Genomics ◽  
Regulatory Networks ◽  
Iron Homeostasis ◽  
Transcriptional Regulatory Networks ◽  
Content Type ◽  
Host Environment ◽  
Regulatory Circuit ◽  
Transcriptional Regulatory ◽  
Cell Host Microbe

ABSTRACT Sadri Znaidi works in the field of molecular mycology with a focus on functional genomics in Candida albicans. In this mSphere of Influence article, he reflects on how the paper “An iron homeostasis regulatory circuit with reciprocal roles in Candida albicans commensalism and pathogenesis” by Chen et al. (C. Chen, K. Pande, S. D. French, B. B. Tuch, and S. M. Noble, Cell Host Microbe 10:118–135, 2011, https://doi.org/10.1016/j.chom.2011.07.005) made an impact on his research on how transcriptional regulatory networks function to control C. albicans’ ability to efficiently interact with the host environment.

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