Systematic gene overexpression in Candida albicans identifies a regulator of early adaptation to the mammalian gut
Ontology highlight
ABSTRACT:
ORGANISM(S): Candida albicans
PROVIDER: GSE67235 | GEO | 2018/11/20
SECONDARY ACCESSION(S): PRJNA279297
REPOSITORIES: GEO
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Project description:Candida albicans is part of the human gastrointestinal (GI) microbiota. To better understand how C. albicans efficiently establishes GI colonisation, we competitively challenged growth of 572 signature-tagged strains (~10% genome coverage), each conditionally overexpressing a single gene, in the murine gut. We identified CRZ2, a transcription factor whose overexpression and deletion respectively increased and decreased early GI colonisation. Using clues from genome-wide expression and gene-set enrichment analyses, we found that the optimal activity of Crz2p occurs under hypoxia at 37°C, as evidenced by both phenotypic and transcriptomic analyses following CRZ2 genetic perturbation. Consistent with early colonisation of the GI tract, we show that CRZ2 overexpression confers resistance to acidic pH and bile salts, suggesting an adaptation to the upper sections of the gut. Genome-wide location analyses revealed that Crz2p directly modulates the expression of many mannosyltransferase- and cell-wall protein-encoding genes, suggesting a link with cell-wall function. We show that CRZ2 overexpression alters cell-wall phosphomannan abundance and increases sensitivity to tunicamycin, suggesting a role in protein glycosylation. Our study reflects the powerful use of gene overexpression as a complementary approach to gene deletion to identify relevant biological pathways involved in C. albicans interaction with the host environment.
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Project description:Among ?5,000,000 fungal species, C. albicans is exceptional in its lifelong association with humans, either within the gastrointestinal microbiome or as an invasive pathogen. Opportunistic infections are generally ascribed to defective host immunity but may require specific microbial programs. Here we report that exposure of C. albicans to the mammalian gut triggers a developmental switch, driven by the Wor1 transcription factor, to a commensal cell type. Wor1 expression was previously observed only in rare genetic backgrounds, where it controls a white-opaque switch in mating. We show that passage of wild-type cells through the mouse gastrointestinal tract triggers WOR1 expression and a novel phenotypic switch. The resulting GUT (gastrointestinally induced transition) cells differ morphologically and functionally from previously defined cell types, including opaque cells, and express a transcriptome that is optimized for the digestive tract. The white-GUT switch illuminates how a microorganism can use distinct genetic programs to transition between commensalism and invasive pathogenesis.
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Project description:The transcriptional regulator Wor1 has been shown to induce the GUT transition, an environmentally triggered process that increases the fitness of Candida albicans in the mouse gastrointestinal tract. We have developed strains where the expression of this gene is driven from the strong and tightly regulated tetracycline promoter. These cells retain the main characteristics reported for GUT cells albeit they show defects in the initial stages of colonization. They also show a differential colonization along the gastrointestinal tract compared to isogenic strains, which is probably caused by their susceptibility to bile salts. We also show that WOR1 overexpressing cells have an altered metabolic activity, as revealed by a different susceptibility to inhibitors of respiration, and an enhanced adhesion to the mouse mucosa. We propose that this may contribute to their long-term favored ability to colonize the gastrointestinal tract.
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Project description:Candida albicans is an opportunistic fungal pathogen that is highly resistant to different oxidative stresses. How reactive sulfur species (RSS) such as sulfite regulate gene expression and the role of the transcription factor Zcf2 and the sulfite exporter Ssu1 in such responses are not known. Here, we show that C. albicans specifically adapts to sulfite stress and that Zcf2 is required for that response as well as induction of genes predicted to remove sulfite from cells and to increase the intracellular amount of a subset of nitrogen metabolites. Analysis of mutants in the sulfate assimilation pathway show that sulfite conversion to sulfide accounts for part of sulfite toxicity and that Zcf2-dependent expression of the SSU1 sulfite exporter is induced by both sulfite and sulfide. Mutations in the SSU1 promoter that selectively inhibit induction by the reactive nitrogen species (RNS) nitrite, a previously reported activator of SSU1, support a model for C. albicans in which Cta4-dependent RNS induction and Zcf2-dependent RSS induction are mediated by parallel pathways, different from S. cerevisiae in which the transcription factor Fzf1 mediates responses to both RNS and RSS. Lastly, we found that endogenous sulfite production leads to an increase in resistance to exogenously added sulfite. These results demonstrate that C. albicans has a unique response to sulfite that differs from the general oxidative stress response, and that adaptation to internal and external sulfite is largely mediated by one transcription factor and one effector gene.
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Project description:Oral Candida albicans has been detected in children with early childhood caries (ECC) and has demonstrated cariogenic traits in animal models of the disease. Conversely, other studies found no positive correlation between C. albicans and caries experience in children, while suggesting it may have protective effects as a commensal organism. Thus, this study aimed to examine whether oral C. albicans is associated with ECC. Seven electronic databases were searched. The data from eligible studies were extracted, and the risk of bias was evaluated. A fixed effects model (Mantel-Haenszel estimate) was used for meta-analysis, and the summary effect measure was calculated by odds ratio (OR) and 95% confidence interval (CI). Fifteen cross-sectional studies were included for the qualitative assessment and 9 studies for meta-analysis. Twelve studies revealed higher oral C. albicans prevalence in ECC children than in caries-free children, while 2 studies indicated an equivalent prevalence. A pooled estimate, with OR = 6.51 and 95% CI = 4.94-8.57, indicated a significantly higher ECC experience in children with oral C. albicans than those without C. albicans (p < 0.01). The odds of experiencing ECC in children with C. albicans versus children without C. albicans were 5.26 for salivary, 6.69 for plaque, and 6.3 for oral swab samples. This systematic review indicates that children with oral C. albicans have >5 times higher odds of having ECC compared to those without C. albicans. Further prospective cohort studies are needed to determine whether C. albicans could be a risk factor for ECC, and whether it is dependent on different sample sources (saliva/plaque).
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Project description:Efg1p is a key transcriptional regulator in Candida albicans which controls various aspects of morphogenesis and metabolism in this organism. Efg1p contains a central basic helix-loop-helix (bHLH) domain, flanked by sequences highly conserved in fungal APSES proteins, as well as polyglutamine stretches at the N- and C-terminal ends. A systematic deletion approach to specify functional domains of Efg1p revealed that the APSES domain is essential for morphogenesis of the normal yeast and true hyphal cell forms and that bHLH flanking sequences are needed for Efg1p stability. Additional C-terminal sequences were required for hyphal formation on some inducing media, and most Efg1p sequences were needed for chlamydospore morphogenesis. Overexpression of EFG1 led to pseudohypha formation only if a functional APSES domain was present, while a switch from the opaque to the white cell type in addition depended on the presence of certain N- and C-terminal segments. Yeast two-hybrid experiments revealed that binding of Efg1p to its antagonist Czf1p required two regions outside of the APSES domain, which did not coincide with Efg1p sequences needed for its transcriptional repressor activity. Binding of the Flo8 transcription factor to Efg1p did not require the APSES domain but appeared to occur at two or more redundant domains. In contrast, DNA binding of Efg1p to an MluI cell cycle box (MCB) element solely required the APSES domain. Overall, these results suggest that functional domains of Efg1p are spread throughout most of its sequences, including the central APSES domain involved in DNA binding, as well as flanking regions required for various protein interactions and regulatory activities.
| S-EPMC2394972 | biostudies-literature
Project description:We report here the identification and characterization of a previously uncharacterized, two-component response regulator gene (orf19.5843) from Candida albicans. Because of its apparent functions in stress adaptation, we have named this gene SRR1 (stress response regulator 1). Disruption of SRR1 causes defects in hyphal development, reduced resistance to stress, and severe virulence attenuation in the mouse model of disseminated candidiasis.
| S-EPMC3187061 | biostudies-literature
Project description:Goal: We employed RNA-seq to identify targets of regulation of five Candida albicans transcription regulators (Try4, Zfu2 and Zcf8). These regulators were identifyed through a genetic screen in a gnotobiotic mouse model of Candida albicans gut colonization. Results: We found that the five regulators comprise a complex transcriptional network (>500 targets of regulation) that partitions in two sub-networks. One sub-network is formed by Rtg1 and Rtg3. The other comprises the regulators Try4, Zfu2 and Zcf8.
2017-08-01 | GSE96547 | GEO
Project description:Among ~5,000,000 fungal species on Earth, Candida albicans is exceptional in its lifelong association with humans, where it exists either as a benign component of the gastrointestinal microbiome or as an invasive pathogen. Although it is generally assumed that invasiveness results from a breakdown of host immunity , it is also possible that specific fungal programs control the transition between these divergent lifestyles. Here, we report that exposure of C. albicans to the mammalian gut triggers a developmental switch, driven by the Wor1 transcription factor, to a commensal cell type. Wor1 has been thought to occur only in unique genetic backgrounds, but we show that WOR1 expression is triggered when wild-type cells are propagated in a murine gastrointestinal infection model. Similar to Wor1’s role in a white-opaque switch for mating, WOR1 overexpression within the host induces a novel switch affecting cell and colony morphology and conferring commensal fitness. However, these hyperfit GUT (Gastrointestinally-IndUced Transition) cells lack the functional hallmarks of opaque cells, which they resemble morphologically, whereas bona fide opaque cells are defective for commensalism. Instead, the GUT cell transcriptome is optimized for the environment of the distal mammalian digestive tract. The GUT cell type switch illuminates how a single organism can utilize distinct genetic programs to transition between commensalism and invasive tissue pathogenesis
2013-07-28 | GSE43972 | GEO
Project description:Hypoxia is encountered frequently by Candida albicans during systemic infection of the human host. We tested if hypoxia allows biofilm formation by C. albicans, which is a major cause of perseverance and antifungal resistance in C. albicans infections. Using an in vitro biofilm system, we unexpectedly discovered that several positive regulators of biofilm formation during normoxia, including Tec1, Ace2, Czf1, Och1, and Als3, had little or no influence on biofilm development during hypoxia, irrespective of the carbon dioxide level, indicating that C. albicans biofilm pathways differ depending on the oxygen level. In contrast, the Efg1 and Flo8 regulators were required for both normoxic and hypoxic biofilm formation. To explore the role of Efg1 during hypoxic and/or biofilm growth, we determined transcriptome kinetics following release of EFG1 expression by a system under transcriptional control of a doxycycline-inducible promoter. During hypoxia, Efg1 rapidly induced expression of all major classes of genes known to be associated with normoxic biofilm formation, including genes involved in glycolysis, sulfur metabolism, and antioxidative and peroxisome activities, as well as genes for iron uptake. The results suggest that hypoxic adaptation mediated by the Efg1 and Flo8 regulators is required even during normoxic biofilm development, while hypoxic biofilm formation in deep tissues or in organs may generate foci of C. albicans infections.
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