New “haploid biofilm model” unravels IRA2 as a novel regulator of Candida albicans biofilm formation

Seneviratne, Chaminda Jayampath; Zeng, Guisheng; Truong, Thuyen; Sze, Sarah; Wong, Sarah Sze Wah; Samaranayake, LP; Chan, Fong Yee; Wang, Yanming; Wang, Haitao; Gao, Jiaxin; Wang, Yue

doi:10.1038/srep12433

Cited by 21 publications

(30 citation statements)

References 42 publications

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“…The recent discovery of haploid strains of C. albicans and subsequent validation of a haploid biofilm model has offered a new toolbox necessary for genetic manipulation in C. albicans research (13). In this study, we performed a comparative proteomics analysis on haploid and diploid C. albicans biofilms and targeted gene expression study to uncover AHP1 as a pivotal antioxidant for the survival of persister cells against amphotericin B.…”

Section: Discussionmentioning

confidence: 99%

“…IRA2 deletion was associated with defective biofilms characterized by reduced structural complexity (13). Next, we queried whether the ira2⌬/⌬ biofilm is associated with reduced antifungal susceptibility like the ahp1⌬/⌬ biofilm.…”

Section: Ahp1⌬/⌬ C Albicans Biofilms Exhibited Reduced Persister Popmentioning

confidence: 99%

“…Biofilm Formation-Biofilm development methodology was adapted from our well-established protocol (13,14). For each strain, single colonies were inoculated in liquid GMM supplemented with required amino acids and incubated at 30°C overnight.…”

Section: Experiments Proceduresmentioning

confidence: 99%

“…Methods-Biofilms were quantified using 2, 3-bis (2-methoxy-4-nitro-5-16 sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay and/or colony forming unit (CFU) counting method as previously described (13). For XTT assay, biofilms were incubated with XTT solution (4 M of menadione and 0.2 mg/ml of XTT in PBS) at 37°C and kept in dark for 20 min.…”

Section: Quantification Of Biofilms By Xtt and Colony Forming Unitmentioning

confidence: 99%

“…In the present study, we took advantage of the recently discovered haploid strains of C. albicans (10) to uncover the mechanism behind the higher persistence of the C. albicans biofilms against amphotericin B, a drug known as "goldstandard" antifungal agent (11). We previously developed an efficient molecular method to generate mutants from haploid C. albicans (12) and used a novel haploid biofilm model of C. albicans to unravel a novel biofilm regulator (13).…”

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confidence: 99%

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Comparative Ploidy Proteomics of Candida albicans Biofilms Unraveled the Role of the AHP1 Gene in the Biofilm Persistence Against Amphotericin B

Truong

Zeng

Lin

et al. 2016

Molecular & Cellular Proteomics

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Candida albicans is a major fungal pathogen causing lethal infections in immunocompromised patients. C. albicans forms antifungal tolerant biofilms contributing significantly to therapeutic failure. The recently established haploid C. albicans biofilm model provides a new toolbox to uncover the mechanism governing the higher antifungal tolerance of biofilms. Here, we comprehensively examined the proteomics and antifungal susceptibility of standard diploid (SC5314 and BWP17) and stable haploid (GZY792 and GZY803) strains of C. albicans biofilms. Subsequent downstream analyses identified alkyl hydroperoxide reductase 1 (AHP1) as a critical determinant of C. albicans biofilm's tolerance of amphotericin B. At 32 g/ml of amphotericin B, GZY803 haploid biofilms showed 0.1% of persister population as compared with 1% of the diploid biofilms. AHP1 expression was found to be lower in GZY803 biofilms, and AHP1 overexpression in GZY803 restored the percentage of persister population. Consistently, deleting AHP1 in the diploid strain BWP17 caused a similar increase in amphotericin B susceptibility. AHP1 expression was also positively correlated with the antioxidant potential. Furthermore, C. albicans ira2⌬/⌬ biofilms were susceptible to amphotericin B and had a diminished antioxidant capacity. Interestingly, AHP1 overexpression in the ira2⌬/⌬ strain restored the antioxidant potential and enhanced the persister population against amphotericin B, and shutting down the AHP1 expression in ira2⌬/⌬ biofilms reversed the effect. In conclusion, we provide evidence that the AHP1 gene critically determines the amphotericin B tolerance of C. albicans biofilms possibly by maintaining the persisters' antioxidant capacity. This finding will open up new avenues for developing therapies targeting the persister population of C. albicans biofilms. The mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD004274. Molecular & Cellular

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Section: Discussionmentioning

confidence: 99%

Section: Ahp1⌬/⌬ C Albicans Biofilms Exhibited Reduced Persister Popmentioning

confidence: 99%

Section: Experiments Proceduresmentioning

confidence: 99%

Section: Quantification Of Biofilms By Xtt and Colony Forming Unitmentioning

confidence: 99%

mentioning

confidence: 99%

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Comparative Ploidy Proteomics of Candida albicans Biofilms Unraveled the Role of the AHP1 Gene in the Biofilm Persistence Against Amphotericin B

Truong

Zeng

Lin

et al. 2016

Molecular & Cellular Proteomics

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Proteomics Analysis of Candida albicans dnm1 Haploid Mutant Unraveled the Association between Mitochondrial Fission and Antifungal Susceptibility

et al. 2019

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Candida albicans is a major fungal pathogen, accounting for approximately 15% of healthcare infections with associated mortality as high as 40% in the case of systemic candidiasis. Antifungal agents for C. albicans infections are limited, and rising resistance is an inevitable problem. Therefore, understanding the mechanism behind antifungal responses is among the top research focuses in combating Candida infections. Herein, the recently developed C. albicans haploid model is employed to examine the association between mitochondrial fission, regulated by Dnm1, and the pathogen's response to antifungals. Proteomic analysis of dnm1Δ and its wild‐type haploid parent, GZY803, reveal changes in proteins associated with mitochondrial structures and functions, cell wall, and plasma membrane. Antifungal susceptibility testing revealed that dnm1Δ is more susceptible to SM21, a novel antifungal, than GZY803. Analyses of reactive oxygen species release, antioxidant response, lipid peroxidation, and membrane damages uncover an association between dnm1Δ and the susceptibility to SM21. Dynasore‐induced mitochondrial inhibition in SC5314 diploids corroborate the findings. Interestingly, Dynasore‐primed SC5314 cultures exhibit increased susceptibility to all antifungals tested. These data suggest an important contribution of mitochondrial fission in antifungal susceptibility of C. albicans. Hence, mitochondrial fission can be a potential target for combined therapy in anti‐C. albicans treatment.

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Genome Diversity and Dynamics in Candida albicans

d’Enfert

Bougnoux

Feri

et al. 2017

Candida Albicans: Cellular and Molecular Biology

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New “haploid biofilm model” unravels IRA2 as a novel regulator of Candida albicans biofilm formation

Cited by 21 publications

References 42 publications

Comparative Ploidy Proteomics of Candida albicans Biofilms Unraveled the Role of the AHP1 Gene in the Biofilm Persistence Against Amphotericin B

Comparative Ploidy Proteomics of Candida albicans Biofilms Unraveled the Role of the AHP1 Gene in the Biofilm Persistence Against Amphotericin B

Proteomics Analysis of Candida albicans dnm1 Haploid Mutant Unraveled the Association between Mitochondrial Fission and Antifungal Susceptibility

Genome Diversity and Dynamics in Candida albicans

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