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Regulatory network modelling of iron acquisition by a fungal pathogen in contact with epithelial cells.

ABSTRACT: BACKGROUND: Reverse engineering of gene regulatory networks can be used to predict regulatory interactions of an organism faced with environmental changes, but can prove problematic, especially when focusing on complicated multi-factorial processes. Candida albicans is a major human fungal pathogen. During the infection process, this fungus is able to adapt to conditions of very low iron availability. Such adaptation is an important virulence attribute of virtually all pathogenic microbes. Understanding the regulation of iron acquisition genes will extend our knowledge of the complex regulatory changes during the infection process and might identify new potential drug targets. Thus, there is a need for efficient modelling approaches predicting key regulatory events of iron acquisition genes during the infection process. RESULTS: This study deals with the regulation of C. albicans iron uptake genes during adhesion to and invasion into human oral epithelial cells. A reverse engineering strategy is presented, which is able to infer regulatory networks on the basis of gene expression data, making use of relevant selection criteria such as sparseness and robustness. An exhaustive use of available knowledge from different data sources improved the network prediction. The predicted regulatory network proposes a number of new target genes for the transcriptional regulators Rim101, Hap3, Sef1 and Tup1. Furthermore, the molecular mode of action for Tup1 is clarified. Finally, regulatory interactions between the transcription factors themselves are proposed. This study presents a model describing how C. albicans may regulate iron acquisition during contact with and invasion of human oral epithelial cells. There is evidence that some of the proposed regulatory interactions might also occur during oral infection. CONCLUSIONS: This study focuses on a typical problem in Systems Biology where an interesting biological phenomenon is studied using a small number of available experimental data points. To overcome this limitation, a special modelling strategy was used which identifies sparse and robust networks. The data is augmented by an exhaustive search for additional data sources, helping to make proposals on regulatory interactions and to guide the modelling approach. The proposed modelling strategy is capable of finding known regulatory interactions and predicts a number of yet unknown biologically relevant regulatory interactions.

SUBMITTER: Linde J

PROVIDER: S-EPMC3225834 | biostudies-other | 2010

REPOSITORIES: biostudies-other

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Regulatory network modelling of iron acquisition by a fungal pathogen in contact with epithelial cells.

Linde Jörg J Wilson Duncan D Hube Bernhard B Guthke Reinhard R

BMC systems biology 20101104

<h4>Background</h4>Reverse engineering of gene regulatory networks can be used to predict regulatory interactions of an organism faced with environmental changes, but can prove problematic, especially when focusing on complicated multi-factorial processes. Candida albicans is a major human fungal pathogen. During the infection process, this fungus is able to adapt to conditions of very low iron availability. Such adaptation is an important virulence attribute of virtually all pathogenic microbes ...[more]

PMID: 21050438

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Project description:BackgroundThe Gram-negative bacterium Yersinia pestis is the causative agent of the bubonic plague. Efficient iron acquisition systems are critical to the ability of Y. pestis to infect, spread and grow in mammalian hosts, because iron is sequestered and is considered part of the innate host immune defence against invading pathogens. We used a proteomic approach to determine expression changes of iron uptake systems and intracellular consequences of iron deficiency in the Y. pestis strain KIM6+ at two physiologically relevant temperatures (26 degrees C and 37 degrees C).ResultsDifferential protein display was performed for three Y. pestis subcellular fractions. Five characterized Y. pestis iron/siderophore acquisition systems (Ybt, Yfe, Yfu, Yiu and Hmu) and a putative iron/chelate outer membrane receptor (Y0850) were increased in abundance in iron-starved cells. The iron-sulfur (Fe-S) cluster assembly system Suf, adapted to oxidative stress and iron starvation in E. coli, was also more abundant, suggesting functional activity of Suf in Y. pestis under iron-limiting conditions. Metabolic and reactive oxygen-deactivating enzymes dependent on Fe-S clusters or other iron cofactors were decreased in abundance in iron-depleted cells. This data was consistent with lower activities of aconitase and catalase in iron-starved vs. iron-rich cells. In contrast, pyruvate oxidase B which metabolizes pyruvate via electron transfer to ubiquinone-8 for direct utilization in the respiratory chain was strongly increased in abundance and activity in iron-depleted cells.ConclusionsMany protein abundance differences were indicative of the important regulatory role of the ferric uptake regulator Fur. Iron deficiency seems to result in a coordinated shift from iron-utilizing to iron-independent biochemical pathways in the cytoplasm of Y. pestis. With growth temperature as an additional variable in proteomic comparisons of the Y. pestis fractions (26 degrees C and 37 degrees C), there was little evidence for temperature-specific adaptation processes to iron starvation.

Project description:Regulation of iron acquisition genes is critical for microbial survival under both iron-limiting conditions (to acquire essential iron) and iron-replete conditions (to limit iron toxicity). In fungi, iron acquisition genes are repressed under iron-replete conditions by a conserved GATA transcriptional regulator. Here we investigate the role of this transcription factor, Sre1, in the cellular responses of the fungal pathogen Histoplasma capsulatum to iron. We showed that cells in which SRE1 levels were diminished by RNA interference were unable to repress siderophore biosynthesis and utilization genes in the presence of abundant iron, and thus produced siderophores even under iron-replete conditions. Mutation of a GATA-containing consensus site found in the promoters of these genes also resulted in inappropriate gene expression under iron-replete conditions. Microarray analysis comparing control and SRE1-depleted strains under conditions of iron limitation or abundance revealed both iron-responsive genes and Sre1-dependent genes, which comprised distinct but overlapping sets. Iron-responsive genes included putative oxidoreductases, metabolic and mitochondrial enzymes, superoxide dismutase, and nitrosative-stress response genes; Sre1-dependent genes were of diverse function. Genes regulated by iron levels and Sre1 included all of the siderophore biosynthetic genes, a gene involved in reductive iron acquisition, an iron-responsive transcription factor, and two catalases. Based on transcriptional profiling and phenotypic analyses, we conclude that Sre1 plays a critical role in the regulation of both traditional iron-responsive genes and iron-independent pathways such as regulation of cell morphology. These data highlight the evolving realization that the effect of Sre1 orthologs on fungal biology extends beyond the iron regulon. For microarray studies, initial cultures of HcLH120 (Control RNAi-1) or 123 (SRE1 RNAi-2) yeast cells were grown in 5 mL HMM, and then passaged 1:25 into 100 mL HMM. After 2 days of growth, the cultures were pelleted, washed in 100 mL of PBS, resuspended in 100 mL of mRPMI pH 6.5 and diluted to an OD600~2 in 1 L of mRPMI. After 24 hours of growth, 200 mL of culture was harvested for each of the three zero time points. Then the cultures were split into 2 X 400 mL, and 10 uM FeSO4 (final concentration) was added to one set of cultures. At each time point (.5, 1, 4, or 8 hours), 100 mL of culture was harvested for RNA extraction.

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Regulatory network modelling of iron acquisition by a fungal pathogen in contact with epithelial cells.

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Regulatory network modelling of iron acquisition by a fungal pathogen in contact with epithelial cells.

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