Dataset Information

Global screening of potential Candida albicans biofilm-related transcription factors via network comparison.

ABSTRACT:

Background

Candida albicans is a commonly encountered fungal pathogen in humans. The formation of biofilm is a major virulence factor in C. albicans pathogenesis and is related to antidrug resistance of this organism. Although many factors affecting biofilm have been analyzed, molecular mechanisms that regulate biofilm formation still await to be elucidated.

Results

In this study, from the gene regulatory network perspective, we developed an efficient computational framework, which integrates different kinds of data from genome-scale analysis, for global screening of potential transcription factors (TFs) controlling C. albicans biofilm formation. S. cerevisiae information and ortholog data were used to infer the possible TF-gene regulatory associations in C. albicans. Based on TF-gene regulatory associations and gene expression profiles, a stochastic dynamic model was employed to reconstruct the gene regulatory networks of C. albicans biofilm and planktonic cells. The two networks were then compared and a score of relevance value (RV) was proposed to determine and assign the quantity of correlation of each potential TF with biofilm formation. A total of twenty-three TFs are identified to be related to the biofilm formation; ten of them are previously reported by literature evidences.

Conclusions

The results indicate that the proposed screening method can successfully identify most known biofilm-related TFs and also identify many others that have not been previously reported. Together, this method can be employed as a pre-experiment screening approach that reveals new target genes for further characterization to understand the regulatory mechanisms in biofilm formation, which can serve as the starting point for therapeutic intervention of C. albicans infections.

SUBMITTER: Wang YC

PROVIDER: S-EPMC2842261 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Publications

Global screening of potential Candida albicans biofilm-related transcription factors via network comparison.

Wang Yu-Chao YC Lan Chung-Yu CY Hsieh Wen-Ping WP Murillo Luis A LA Agabian Nina N Chen Bor-Sen BS

BMC bioinformatics 20100126

<h4>Background</h4>Candida albicans is a commonly encountered fungal pathogen in humans. The formation of biofilm is a major virulence factor in C. albicans pathogenesis and is related to antidrug resistance of this organism. Although many factors affecting biofilm have been analyzed, molecular mechanisms that regulate biofilm formation still await to be elucidated.<h4>Results</h4>In this study, from the gene regulatory network perspective, we developed an efficient computational framework, whic ...[more]

PMID: 20102611

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Project description:Candida albicans is a fungal species that is part of the normal human microbiota and also an opportunistic pathogen capable of causing mucosal and systemic infections. C. albicans cells proliferate in a planktonic (suspension) state, but they also form biofilms, organized and tightly packed communities of cells attached to a solid surface. Biofilms colonize many niches of the human body and persist on implanted medical devices, where they are a major source of new C. albicans infections. Here, we used an unbiased and global substrate-profiling approach to discover proteolytic activities produced specifically by C. albicans biofilms, compared to planktonic cells, with the goal of identifying potential biofilm-specific diagnostic markers and targets for therapeutic intervention. This activity-based profiling approach, coupled with proteomics, identified Sap5 (Candidapepsin-5) and Sap6 (Candidapepsin-6) as major biofilm-specific proteases secreted by C. albicans Fluorogenic peptide substrates with selectivity for Sap5 or Sap6 confirmed that their activities are highly upregulated in C. albicans biofilms; we also show that these activities are upregulated in other Candida clade pathogens. Deletion of the SAP5 and SAP6 genes in C. albicans compromised biofilm development in vitro in standard biofilm assays and in vivo in a rat central venous catheter biofilm model. This work establishes secreted proteolysis as a promising enzymatic marker and potential therapeutic target for Candida biofilm formation. Biofilm formation by the opportunistic fungal pathogen C. albicans is a major cause of life-threatening infections. This work provides a global characterization of secreted proteolytic activity produced specifically by C. albicans biofilms. We identify activity from the proteases Sap5 and Sap6 as highly upregulated during C. albicans biofilm formation and develop Sap-cleavable fluorogenic substrates that enable the detection of biofilms from C. albicans and also from additional pathogenic Candida species. Furthermore, SAP5 and SAP6 deletions confirm that both proteases are required for proper biofilm development in vitro and in vivo We propose that secreted proteolysis is a promising marker for the diagnosis and potential therapeutic targeting of Candida biofilm-associated infections.

Project description:Polymicrobial biofilms play important roles in oral and systemic infections. The oral plaque bacterium Streptococcus gordonii is known to attach to the hyphal cell wall of the fungus Candida albicans to form corn-cob like structures in biofilms. However, the role of C. albicans in formation of polymicrobial biofilms is not completely understood. The objective of this study was to determine the role of C. albicans transcription factors in regulation of polymicrobial biofilms and antibiotic tolerance of S. gordonii. The proteins secreted by C. albicans and S. gordonii in mixed planktonic cultures were determined using mass spectrometry. Antibiotic tolerance of S. gordonii to ampicillin and erythromycin was determined in mixed cultures and mixed biofilms with C. albicans. Additionally, biofilm formation of S. gordonii with C. albicans knock-out mutants of 45 transcription factors that affect cell wall integrity, filamentous growth and biofilm formation was determined. Furthermore, these mutants were also screened for antibiotic tolerance in mixed biofilms with S. gordonii. Analysis of secreted proteomes resulted in the identification of proteins being secreted exclusively in mixed cultures. Antibiotic testing showed that S. gordonii had significantly increased survival in mixed planktonic cultures with antibiotics as compared to single cultures. C. albicans mutants of transcription factors Sfl2, Brg1, Leu3, Cas5, Cta4, Tec1, Tup1, Rim101 and Efg1 were significantly affected in mixed biofilm formation. Also mixed biofilms of S. gordonii with mutants of C. albicans transcription factors, Tec1 and Sfl2, had significantly reduced antibiotic tolerance as compared to control cultures. Our data indicates that C. albicans may have an important role in mixed biofilm formation as well as antibiotic tolerance of S. gordonii in polymicrobial biofilms. C. albicans may play a facilitating role than being just an innocent bystander in oral biofilms and infections.

Dataset Information

Global screening of potential Candida albicans biofilm-related transcription factors via network comparison.

Background

Results

Conclusions

Publications

Global screening of potential Candida albicans biofilm-related transcription factors via network comparison.

Similar Datasets

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