Candida albicans Commensalism and Pathogenicity Are Intertwined Traits Directed by a Tightly Knit Transcriptional Regulatory Circuit

Pérez, J. Christian; Kumamoto, Carol A.; Johnson, Alexander D.

doi:10.1371/journal.pbio.1001510

Cited by 140 publications

(225 citation statements)

References 60 publications

(93 reference statements)

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“…Interestingly, C. albicans stays mostly as the yeast form in the GI tract (42). Farnesol may play a role, because the cup9 mutant displayed slightly increased colonization in the GI tract in a mouse model of intestinal colonization with pooled mutants (43). In addition to farnesol, other quorumsensing molecules in the host's gut microbiota may also regulate hyphal development of C. albicans.…”

Section: Discussionmentioning

confidence: 99%

Quorum sensing controls hyphal initiation in Candida albicans through Ubr1-mediated protein degradation

Lü

Unoje

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

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Candida albicans is the most common cause of invasive fungal infections in humans. Its ability to undergo the morphological transition from yeast to hyphal growth forms is critical for its pathogenesis. Hyphal initiation requires the activation of the cAMP-PKA pathway, which down-regulates the expression of NRG1, the major repressor of hyphal development. Hyphal initiation also requires inoculation of a small amount of C. albicans cells from overnight culture to fresh medium. This inoculation releases the inhibition from farnesol, a quorum-sensing molecule of C. albicans, that accumulated in the spent medium. Here, we show that farnesol inhibits hyphal initiation mainly through blocking the protein degradation of Nrg1. Through screening a kinase mutant library, we identified Sok1 as the kinase required for Nrg1 degradation during inoculation. SOK1 expression is transiently activated on inoculation during hyphal initiation, and overexpression of SOK1 overcomes the farnesol-mediated inhibition of hyphal initiation. Screening a collection of transcription factor mutants, the homeodomain-containing transcription repressor Cup9 is found to be responsible for the repression of SOK1 expression in response to farnesol inhibition. Interestingly, farnesol inhibits Cup9 degradation mediated by the N-end rule E3 ubiquitin ligase, Ubr1. Therefore, hyphal initiation requires both the cAMP-PKA pathway-dependent transcriptional down-regulation of NRG1 and Sok1-mediated degradation of Nrg1 protein. The latter is triggered by the release from farnesol inhibition of Cup9 degradation and consequently, derepression of SOK1 transcription. Neither pathway alone is sufficient for hyphal initiation.

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Section: Discussionmentioning

confidence: 99%

Quorum sensing controls hyphal initiation in Candida albicans through Ubr1-mediated protein degradation

Lü

Unoje

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

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“…Opportunistic infections by commensal organisms are unique from other types of microbial infection, because they are caused by microbiota that is already present in the host. The mechanistic switch between the commensal and pathogenic state is not well understood, but commensal and pathogenic proliferation appears to be controlled by the same genetic circuit [21]. C. albicans has extensive cellular machinery to respond to metal availability in the host environment; therefore, nutritional immunity is likely to be one mechanism that controls proliferation and pathogenesis of commensal Candida in the human oral environment.…”

Section: Introductionmentioning

confidence: 99%

Salivary metals, age, and gender correlate with cultivable oral Candida carriage levels

Norris

Friedman

Chen

et al. 2018

Journal of Oral Microbiology

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Background: Little is known about the normal range of metal levels in unstimulated saliva, nor whether these might impact Candida carriage in healthy individuals. Both are important in determining which populations are at risk for candidiasis, as the availability of metal ions can influence the growth and pathogenesis of Candida albicans. Objective: We quantified salivary metals of healthy individuals to determine the correlation with C. albicans oral colonization. Design: Unstimulated whole saliva was collected from healthy adults and plated to determine fungal carriage, and metal content was measured using ICP-mass spectrometry (ICP-MS). Results: Zinc was most abundant, followed by iron, copper, manganese, and nickel. Cultivable oral Candida carriage was found in 48% of people. Total protein levels did not differ in salivas from donors with or without carriage. However, innate fungicidal activity was increased in donors with carriage; correlations between levels of several metals were stronger in salivas with fungal carriage, indicating a shift in the oral environment. Concentrations of copper and manganese, as well as age and gender, were significantly predictive of carriage levels in a multiple regression model. Conclusions: Salivary copper and manganese content along with age and gender could be used as a predictive metric for individuals that are more susceptible to Candida overgrowth.

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“…27 LYS14 binds upstream of genes encoding enzymes predicted to modify the cell surface of the fungus, and thus it may play a role in immune evasion; consistent with this observation, the C. albicans lys14 mutant shows reduced virulence in a murine model of systemic infection. 27 Taken together, these findings indicate that each of the duplicated LYS regulators has a unique role in C. albicans biology. While the function of LYS142 remains to be uncovered, clearly the other 3 homologs control functions that are relevant within the host.…”

Section: Transcriptional Regulation Changes In the Adaptation Of The mentioning

confidence: 56%

“…23 The right side of the figure shows a subset of each regulators' target genes as determined by ChIP-chip. 23,27 Notice that the target genes included here are those that most likely contribute to the ability of C. albicans to colonize its mammalian host and cause disease.…”

Section: Fundingmentioning

confidence: 99%

Reshuffling transcriptional circuits: how microorganisms adapt to colonize the human body

Pérez

2014

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Candida albicans Commensalism and Pathogenicity Are Intertwined Traits Directed by a Tightly Knit Transcriptional Regulatory Circuit

Abstract: The identification of regulators, circuits, and target genes employed by the fungus Candida albicans to thrive in disparate niches in a mammalian host reveals interconnection between commensal and pathogenic lifestyles.

Cited by 140 publications

References 60 publications

Quorum sensing controls hyphal initiation in Candida albicans through Ubr1-mediated protein degradation

Quorum sensing controls hyphal initiation in Candida albicans through Ubr1-mediated protein degradation

Salivary metals, age, and gender correlate with cultivable oral Candida carriage levels

Reshuffling transcriptional circuits: how microorganisms adapt to colonize the human body

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