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Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance
Open accessAbstract
Fungal pathogens pose a serious threat to public health. Candida auris is an emerging fungal pathogen that is often resistant to commonly used antifungal drugs. However, the mechanisms governing drug resistance and virulence in this organism remain largely unexplored. In this study, we adapted a conditional expression system to modulate the transcription of an essential gene, HSP90 , which regulates antifungal resistance and virulence in diverse fungal pathogens. We showed that Hsp90 is essential for growth in C. auris and is important for tolerance of the clinically important azole antifungals, which block ergosterol biosynthesis. Further, we established that the Cdr1 efflux transporter regulates azole resistance. Finally, we discovered that C. auris transitions from yeast to filamentous growth in response to Hsp90 inhibition, accompanied by global transcriptional remodeling. Overall, this work provides a novel insight into mechanisms regulating azole resistance in C. auris and uncovers a distinct developmental program regulated by Hsp90.
Overview
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TL;DR
This study adapted a tetracycline-repressible promoter system to show that Hsp90 is essential in *Candida auris*, mediates fluconazole tolerance in some clinical isolates, and represses filamentous growth. It also identifies the Cdr1 efflux transporter as a major contributor to azole resistance in *C. auris*.
Key findings
- Hsp90 is essential in *C. auris*: doxycycline-mediated repression of tetO-HSP90 reduced HSP90 expression to less than 40% of wild-type and caused loss of viable colonies.
- Hsp90 inhibition reduced fluconazole tolerance in *C. auris* clinical isolates CDC-382 and CDC-387 and transformed fluconazole activity from fungistatic to fungicidal, but did not affect high-level resistance in Ci6684 or CDC-388.
- Deletion of CDR1 in strain Ci6684 caused an 8-fold decrease in fluconazole MIC, and CDR1 expression positively correlated with fluconazole MIC50 across clinical isolates (Pearson r = 0.59).
- Hsp90 inhibition or depletion induced filamentous growth in *C. auris* and other CUG-clade species; RNA-Seq identified 2,111 *C. auris* DEGs upon geldanamycin treatment and 1,014 upon HSP90 depletion, with only 292 concordant DEGs.
Methods
- A tetO-HSP90 conditional expression strain was constructed in fluconazole-resistant *C. auris* strain Ci6684 by CRISPR/Cas9-mediated promoter replacement, adapting a *C. albicans* system.
- Drug susceptibility was assessed by spotting assays, fluconazole Etest strips, and checkerboard assays with fluconazole plus geldanamycin; CDR1 was deleted in Ci6684 and fluconazole MICs were measured.
- Morphology was monitored by DIC microscopy after genetic depletion or pharmacological inhibition of Hsp90 and after canonical filament-inducing cues; RNA-Seq was performed in quadruplicate and analyzed with HISAT2, StringTie, and DESeq2.
Limitations
- The paper states that the role of filamentous growth in *C. auris* is unclear, that only one prior study reported filamentation under high salt, and that further exploration of cues and genetic circuitry is needed.
- Evident from the text: CDR1 deletion was tested only in the Ci6684 background, and Hsp90’s role in fluconazole tolerance was limited to a subset of CDC clinical isolates.
- Evident from the text: RNA-Seq used strain Ci6684 but reads were aligned to the B8441 reference genome, and the study notes that depletion and pharmacological inhibition of Hsp90 produced distinct transcriptional responses.
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![FIG 3 Fluconazole resistance is mediated by drug efflux in C. auris. (A) Plot of relative CDR1 expression versus MIC50 in the panel of C. auris isolates. CDR1 transcript levels were normalized against ACT1 and GPD1 transcript levels. MIC50 values were derived from the MIC assay results presented in Fig. 2. The Pearson correlation coefficient (r) was calculated for the two values. (B) MIC assay for fluconazole. Ci6684 (wild type [WT]) and cdr1Δ strains were inoculated with a 2-fold gradient of fluconazole. The plates were incubated at 30°C for 48 h. Data were analyzed as described for Fig. 1C.](/paper-figures/9876462e0fbe45a589800be8a99e449e/genetic-analysis-of-i-candida-auris-i-implicates-hsp90-in-morphogenesis-and-figure-3.jpg)
Verification
Claims the paper makes
47 Own result · 31 Not checked yet · 14 Own interpretation · 4 Own method · 2 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, we discovered that C. auris transitions from yeast to filamentous growth in response to Hsp90 inhibition, accompanied by global transcriptional remodeling.”
- Also stated in: § INTRODUCTION · plain
“we discovered that genetic depletion or pharmacological inhibition of Hsp90 induced filamentous growth in C. auris.”
- Also stated in: § Hsp90 represses filamentous growth in C. auris. · plain
“During characterization of the C. auris tetO-HSP90 strain, we discovered that depletion of HSP90 resulted in polarized growth, similar to what was observed in C. albicans”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > Abstract
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- Also stated in: § INTRODUCTION · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, we discovered that C. auris transitions from yeast to filamentous growth in response to Hsp90 inhibition, accompanied by global transcriptional remodeling.”
- Also stated in: § C. auris filamentation is associated with transcriptional induction of putative cell surface genes. · plain
“We identified global transcriptional changes in response to Hsp90 compromise in both species.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > Abstract
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- Also stated in: § C. auris filamentation is associated with transcriptional induction of putative cell surface genes. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We showed that Hsp90 is essential for growth in C. auris”
- Also stated in: § HSP90 is essential in C. auris. · plain
“Thus, Hsp90 is essential in C. auris, and the tetO promoter system offers a powerful approach for studying essential gene function in this emerging pathogen.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > Abstract
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In the paper
“Compared to Hsp90 depletion, only 744 DEGs in C. albicans showed concordant changes in expression under both conditions (Fig. 6A).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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In the paper
“Many of these genes (ALS1, IFF4, RBT1, and KRE1) were also upregulated upon Hsp90 inhibition and depletion in C. albicans (Fig. 6C).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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In the paper
“However, high doses of the cell cycle arresting agent hydroxyurea induced polarized growth in C. auris, similar to what was observed with C. albicans (Fig. 4B).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 represses filamentous growth in C. auris.
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In the paper
“Hsp90 inhibition reduced the azole tolerance of two C. auris clinical isolates, CDC-382 and CDC-387, and transformed the activity of fluconazole from fungistatic to fungicidal.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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“C. auris did not filament in response to canonical filament-inducing cues for C. albicans, such as serum, Spider medium, RPMI medium, or elevated temperature (Fig. 4C).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 represses filamentous growth in C. auris.
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“Of these, CDC-381 and CDC-382 showed a tolerance phenotype with persistent growth beyond the drug MIC (Fig. 2A).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
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“In the absence of doxycycline, both C. auris and C. albicans were capable of growing at concentrations of fluconazole up to the highest tested (Fig. 1B).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
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“Finally, we discovered a novel filamentation program in C. auris that is negatively regulated by Hsp90.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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“Hsp90 was dispensable for the resistance of several C. auris strains that harbored mutations in ERG11 and high levels of CDR1 expression.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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“As expected, HSP90 was one of the most extensively downregulated transcripts in the depletion data set for both species (Table S1).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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“The transcriptional changes in C. auris were reminiscent of those observed in C. albicans.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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In the paper
“Of these, only 10 transcripts showed an overlap under the two conditions (Fig. 6B).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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“We performed gene ontology (GO) term enrichment analysis of the DEGs in C. albicans and found that inhibition of Hsp90 was associated with upregulation of transcripts involved in mitochondrial respiration and ribosomal processes and with downregulation of transcripts involved in metabolic and biosynthetic processes (Fig. S5A and Table S2).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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In the paper
“As observed with the C. albicans HSP90 conditional expression strain, doxycycline-mediated transcriptional repression of C. auris HSP90 resulted in a lack of viable colonies recovered via spotting (Fig. 1A).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > HSP90 is essential in C. auris.
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In the paper
“Hsp90 inhibition reduced the azole tolerance of two C. auris clinical isolates, CDC-382 and CDC-387, and transformed the activity of fluconazole from fungistatic to fungicidal.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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“Interestingly, the C. auris genome does not contain orthologs of HWP1 or ECE1 (Table S1) (18).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
What the sources say
- Not checked yetcites [18] Muñoz JF, Gade L, Chow NA, Loparev VN, Juieng P, Berkow EL, Farrer RA, Litvintseva AP, Cuomo CA 2018 Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species. Nat Commun 9: 5346. 30559369 PMC6297351 source
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In the paper
“Three clinical isolates, CDC-381, CDC-382, and CDC-387, were more susceptible to fluconazole than the other strains.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
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In the paper
“A further increase in the concentration of doxycycline to 10 μg/ml severely affected growth on its own in both C. albicans and C. auris due to HSP90 essentiality (Fig. 1B).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
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“In addition, YWP1, which encodes a secreted cell wall protein specific to yeast growth (42), was downregulated, further supporting the idea of a filamentous growth program caused by Hsp90 perturbation.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [42] Granger BL, Flenniken ML, Davis DA, Mitchell AP, Cutler JE 2005 Yeast wall protein 1 of Candida albicans. Microbiology 151: 1631– 1644. doi: 10.1099/mic.0.27663-0. 15870471 source
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In the paper
“In addition, genes involved in iron metabolism, such as FTH1 (B9J08_000170), FRE9 (B9J08_000168), and FRP1 (B9J08_004468), were upregulated in both organisms under conditions of filamentous growth”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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“In total, 2,501 and 2,111 DEGs were identified upon inhibition of Hsp90 with geldanamycin in C. albicans and C. auris, respectively (Fig. 6A; see also Table S1 in the supplemental material).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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“Instead, genes orthologous to C. albicans adhesins or adhesin-like proteins such as ALS1 (B9J08_004112), IFF4 (B9J08_004451), PGA26 (B9J08_000117) and to other cell surface proteins such as RBT1 (B9J08_001458), PHR1 (B9J08_000918), and KRE1 (B9J08_005473) were upregulated upon filamentation in C. auris (Table S1).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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In the paper
“Although geldanamycin potentiated fluconazole activity against C. albicans, the combination had no effect on azole susceptibility in C. auris (Fig. 1C).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
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“For C. albicans, GO slim mapping of the DEGs identified 249 and 317 transcripts involved in filamentous growth upon Hsp90 inhibition and depletion, respectively (Fig. 6B; see also Table S3).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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“In response to doxycycline-mediated transcriptional repression of HSP90, 3,331 and 1,014 DEGs were identified in C. albicans and C. auris, respectively (Fig. 6A; see also Table S1).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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“However, exposure to other canonical C. albicans filament-inducing cues had no impact on the yeast-to-filament transition in C. auris.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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“Further, only three genes annotated as involved in filamentous growth, ERG3, ERG1, and DSE1, were found to be downregulated in both species upon perturbation of Hsp90.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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In the paper
“However, the same doxycycline concentration had no effect on growth of the C. auris tetO-HSP90 strain in the presence of fluconazole (Fig. 1B).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
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“Furthermore, the combination transformed the fungistatic activity of fluconazole to fungicidal, as observed upon attempted culturing on drug-free medium following drug exposure (Fig. 2B).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
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In the paper
“Similarly to C. albicans, pharmacological inhibition and genetic depletion of Hsp90 in C. auris induced distinct transcriptional responses, with only 292 DEGs showing concordant changes in expression (Fig. 6A).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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In the paper
“When we compared the MIC50 values of fluconazole for each isolate to their CDR1 expression level, we observed a positive correlation (r [Pearson correlation coefficient] = 0.59) (Fig. 3A)”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90-independent fluconazole resistance is mediated in part by Cdr1.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Further, we identified the Cdr1 ABC transporter as a major contributor to azole resistance in C. auris.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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In the paper
“HSP70 was one of the common transcripts upregulated upon Hsp90 inhibition and depletion in both organisms (Table S1), consistent with induction of HSP70 by activation of the Hsf1 heat shock transcription factor upon Hsp90 inhibition (36).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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In the paper
“In this study, we examined the impact of C. auris Hsp90 on fluconazole resistance and discovered that this molecular chaperone is important for tolerance of fluconazole, potentially enabling the evolution of drug resistance in otherwise susceptible strains.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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In the paper
“Genetic depletion or pharmacological inhibition of Hsp90 had no effect on fluconazole resistance”
- Also stated in: § Hsp90-independent fluconazole resistance is mediated in part by Cdr1. · plain
“Given that Hsp90 had minimal impact on the high level of azole resistance displayed by several C. auris strains”
- Also stated in: § Hsp90 is an important mediator of tolerance in C. auris. · plain
“Notably, geldanamycin did not affect the high-level fluconazole resistance phenotypes of strain Ci6684 or strain CDC-388 or the fungistatic activity of fluconazole against these strains (Fig. 2B).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
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- Also stated in: § Hsp90-independent fluconazole resistance is mediated in part by Cdr1. · plain
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In the paper
“Global transcriptional analysis highlighted that compromise of Hsp90 function was accompanied by transcriptional upregulation of predicted cell surface genes for which the C. albicans orthologs have functional annotations associated with filamentous growth.”
- Also stated in: § C. auris filamentation is associated with transcriptional induction of putative cell surface genes. · plain
“genes orthologous to C. albicans adhesins or adhesin-like proteins such as ALS1 (B9J08_004112), IFF4 (B9J08_004451), PGA26 (B9J08_000117) and to other cell surface proteins such as RBT1 (B9J08_001458), PHR1 (B9J08_000918), and KRE1 (B9J08_005473) were upregulated upon filamentation in C. auris”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
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- Also stated in: § C. auris filamentation is associated with transcriptional induction of putative cell surface genes. · plain
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In the paper
“For strains CDC-382 and CDC-387, geldanamycin abrogated tolerance of fluconazole at concentrations above their fluconazole MICs (Fig. 2B), a result which was also recapitulated in an Etest strip assay (Fig. S2).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
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In the paper
“As expected, incubation of the C. albicans tetO-HSP90/tetO-HSP90 strain with a doxycycline concentration that did not affect growth on its own (0.1 μg/ml) caused hypersensitivity to fluconazole.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Finally, the ortholog of YWP1, encoded by B9J08_001409, was downregulated in response to filamentation in C. auris (Fig. 6A).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“deletion of CDR1 was sufficient to confer an 8-fold increase in the sensitivity of C. auris to fluconazole”
- Also stated in: § Hsp90-independent fluconazole resistance is mediated in part by Cdr1. · plain
“we deleted the CDR1 open reading frame in the Ci6684 background and observed an 8-fold decrease in fluconazole MIC”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
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- Also stated in: § Hsp90-independent fluconazole resistance is mediated in part by Cdr1. · plain
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In the paper
“Further, we established that the Cdr1 efflux transporter regulates azole resistance.”
- Also stated in: § INTRODUCTION · hedged
“deletion of CDR1 was sufficient to confer an 8-fold increase in the sensitivity of C. auris to fluconazole, indicating that this specific efflux transporter plays a pivotal role in azole resistance.”
- Also stated in: § Hsp90-independent fluconazole resistance is mediated in part by Cdr1. · hedged
“suggesting that Cdr1 is a major contributor to azole resistance in C. auris.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > Abstract
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- Also stated in: § INTRODUCTION · hedged
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In the paper
“Further, the identification of many putative transporter genes in the C. auris genome suggests that drug efflux may also be an important determinant of azole resistance (16–18).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [16] Chatterjee S, Alampalli SV, Nageshan RK, Chettiar ST, Joshi S, Tatu US 2015 Draft genome of a commonly misdiagnosed multidrug resistant pathogen Candida auris. BMC Genomics 16: 686. doi: 10.1186/s12864-015-1863-z. 26346253 PMC4562351 source
- Not checked yetcites [17] Sharma C, Kumar N, Pandey R, Meis JF, Chowdhary A 2016 Whole genome sequencing of emerging multidrug resistant Candida auris isolates in India demonstrates low genetic variation. New Microbes New Infect 13: 77– 82. doi: 10.1016/j.nmni.2016.07.003. 27617098 PMC5006800 source
- Not checked yetcites [18] Muñoz JF, Gade L, Chow NA, Loparev VN, Juieng P, Berkow EL, Farrer RA, Litvintseva AP, Cuomo CA 2018 Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species. Nat Commun 9: 5346. 30559369 PMC6297351 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“We showed that Hsp90 is essential for growth in C. auris and is important for tolerance of the clinically important azole antifungals, which block ergosterol biosynthesis.”
- Also stated in: § Hsp90 is an important mediator of tolerance in C. auris. · plain
“For strains CDC-382 and CDC-387, geldanamycin abrogated tolerance of fluconazole at concentrations above their fluconazole MICs”
- Also stated in: § Hsp90 is an important mediator of tolerance in C. auris. · plain
“Overall, our work implicates Hsp90 as an important mediator of fluconazole tolerance in C. auris.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > Abstract
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- Also stated in: § Hsp90 is an important mediator of tolerance in C. auris. · plain
In the paper
“Most alarmingly, some isolates have been reported to show elevated resistance to all three major antifungal classes, leaving no treatment options for such infections (4).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [4] Chowdhary A, Sharma C, Meis JF 2017 Candida auris: a rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally. PLoS Pathog 13: e1006290. doi: 10.1371/journal.ppat.1006290. 28542486 PMC5436850 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Specifically, studies have estimated that as much as 93% of clinical isolates exhibit increased resistance to fluconazole, an azole commonly administered for treating systemic Candida infections (6).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [6] Lockhart SR, Etienne KA, Vallabhaneni S, Farooqi J, Chowdhary A, Govender NP, Colombo AL, Calvo B, Cuomo CA, Desjardins CA, Berkow EL, Castanheira M, Magobo RE, Jabeen K, Asghar RJ, Meis JF, Jackson B, Chiller T, Litvintseva AP 2017 Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis 64: 134– 140. doi: 10.1093/cid/ciw691. 27988485 PMC5215215 source
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests that Hsp90 enables key cellular responses to azole-induced cell membrane stress in C. auris such that inhibition of Hsp90 impairs survival.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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In the paper
“For example, although there is a correlation between S. cerevisiae and C. albicans with respect to their essential genes, the predictive value from S. cerevisiae to C. albicans is only 52% (38), emphasizing the need to characterize essential genes directly in the organism of interest (38, 39).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [38] O'Meara TR, Veri AO, Ketela T, Jiang B, Roemer T, Cowen LE 2015 Global analysis of fungal morphology exposes mechanisms of host cell escape. Nat Commun 6: 6741. doi: 10.1038/ncomms7741. 25824284 PMC4382923 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this study, we examined the impact of C. auris Hsp90 on fluconazole resistance and discovered that this molecular chaperone is important for tolerance of fluconazole, potentially enabling the evolution of drug resistance in otherwise susceptible strains.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed that the tetO-HSP90 strain expressed HSP90 at a higher level than the wild-type control in the absence of the tetracycline analog doxycycline (Fig. S1B).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > HSP90 is essential in C. auris.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“As CDC-382 and CDC-387 do not contain any known Erg11 substitutions associated with azole resistance and show relatively low levels of CDR1 expression, these two isolates may reflect a C. auris state prior to fluconazole exposure and acquisition of mutations associated with resistance (6).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [6] Lockhart SR, Etienne KA, Vallabhaneni S, Farooqi J, Chowdhary A, Govender NP, Colombo AL, Calvo B, Cuomo CA, Desjardins CA, Berkow EL, Castanheira M, Magobo RE, Jabeen K, Asghar RJ, Meis JF, Jackson B, Chiller T, Litvintseva AP 2017 Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis 64: 134– 140. doi: 10.1093/cid/ciw691. 27988485 PMC5215215 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, C. auris is capable of undergoing a distinct morphogenetic transition in response to cell cycle arrest or Hsp90 inhibition.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 represses filamentous growth in C. auris.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The adaptive potential of this pathogen is further emphasized by the finding that most C. auris clinical isolates exhibit extremely high levels of resistance to antifungals, particularly the azoles (4).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [4] Chowdhary A, Sharma C, Meis JF 2017 Candida auris: a rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally. PLoS Pathog 13: e1006290. doi: 10.1371/journal.ppat.1006290. 28542486 PMC5436850 source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, our findings implicate Hsp90 as a central regulator of diverse facets of C. auris biology, including morphogenesis and cellular responses to drug-induced stress.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Therefore, filamentation in response to Hsp90 inhibition appears to be a trait conserved within the CUG clade.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 represses filamentous growth in C. auris.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“suggesting that iron acquisition might be an important facet of the morphogenetic transition in C. auris, as it is in C. albicans (37).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
What the sources say
- Not checked yetcites [37] Almeida RS, Brunke S, Albrecht A, Thewes S, Laue M, Edwards JE, Filler SG, Hube B 2008 the hyphal-associated adhesin and invasin Als3 of Candida albicans mediates iron acquisition from host ferritin. PLoS Pathog 4: e1000217. doi: 10.1371/journal.ppat.1000217. 19023418 PMC2581891 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Upon the addition of doxycycline, HSP90 levels were reduced to less than 40% of that seen with the wild-type control (Fig. S1B).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > HSP90 is essential in C. auris.
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that increased expression of CDR1 may contribute to elevated fluconazole resistance.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90-independent fluconazole resistance is mediated in part by Cdr1.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Although the essentiality of highly conserved genes such as HSP90 is often maintained across eukaryotes, the essential gene sets can diverge significantly between organisms (38).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [38] O'Meara TR, Veri AO, Ketela T, Jiang B, Roemer T, Cowen LE 2015 Global analysis of fungal morphology exposes mechanisms of host cell escape. Nat Commun 6: 6741. doi: 10.1038/ncomms7741. 25824284 PMC4382923 source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While it is clear that the environmental cues that trigger C. auris morphogenesis are largely distinct from those that trigger C. albicans morphogenesis, our results suggest that transcriptional remodeling of the cell surface is conserved during this developmental transition.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While it is clear that the environmental cues that trigger C. auris morphogenesis are largely distinct from those that trigger C. albicans morphogenesis, our results suggest that transcriptional remodeling of the cell surface is conserved during this developmental transition.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
boosted- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- It may state two separate claims as one. 19
- Probably not a substantial claim. 18
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Depletion of HSP90 led to the upregulation of transcripts predicted to be involved in transmembrane transport and downregulation of genes annotated as involved in translation and peptide metabolic processes (Fig. S6 and Table S2).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In total, 28 transcripts were upregulated and 17 transcripts were downregulated upon Hsp90 perturbation in both organisms (Fig. 6C).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“In C. albicans, filamentation caused by perturbations in Hsp90 was associated with upregulation of filament-associated genes such as HWP1, ECE1, and RBT1, consistent with previous reports (21, 41).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [21] Shapiro RS, Sellam A, Tebbji F, Whiteway M, Nantel A, Cowen LE 2012 Pho85, Pcl1, and Hms1 signaling governs Candida albicans morphogenesis induced by high temperature or Hsp90 compromise. Curr Biol 22: 461– 470. doi: 10.1016/j.cub.2012.01.062. 22365851 source
- Not checked yetcites [41] Braun BR, Head WS, Wang MX, Johnson AD 2000 Identification and characterization of TUP1-regulated genes in Candida albicans. Genetics 156: 31– 44. 10978273 PMC1461230 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GO term enrichment analysis of the DEGs in response to Hsp90 inhibition identified upregulation of transcripts involved in ribosomal processes and downregulation of transcripts involved in metabolic and biosynthetic processes (Fig. S6 and Table S2).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of these, 107 transcripts showed an overlap under the two conditions, including known regulators of filamentation HWP1, ECE1, RBT1, BRG1, UME6, EFH1, and BCR1, which were upregulated, and YWP1, which was downregulated (Fig. 6A; see also Table S1).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
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In the paper
“Although geldanamycin potentiated fluconazole activity against C. albicans, the combination had no effect on azole susceptibility in C. auris (Fig. 1C).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“As CDC-382 and CDC-387 do not contain any known Erg11 substitutions associated with azole resistance and show relatively low levels of CDR1 expression, these two isolates may reflect a C. auris state prior to fluconazole exposure and acquisition of mutations associated with resistance (6).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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In the paper
“GO slim mapping of the DEGs identified 79 and 33 transcripts involved in filamentous growth upon Hsp90 inhibition and depletion, respectively, but none of these showed an overlap with the known regulators of C. albicans filamentation identified above (Fig. 6B; see also Table S3).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Here, we showed that the impairment of either Hsp90 function or cell cycle progression also leads to filamentous growth in this pathogen.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
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In the paper
“Interestingly, all species classified within the “CUG” clade showed filamentous growth in response to geldanamycin to various degrees, while the non-CUG clade species remained exclusively in yeast form (Fig. 5).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 represses filamentous growth in C. auris.
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In the paper
“Surprisingly, depletion of HSP90 showed a enrichment profile distinct from that observed upon pharmacological inhibition with Hsp90 in C. albicans, for which transcripts involved in responses to oxidative stress were upregulated and transcripts involved in ribosomal and mitochondrial processes were downregulated (see Fig. S5 and Table S2).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, geldanamycin did not affect the high-level fluconazole resistance phenotypes of strain Ci6684 or strain CDC-388 or the fungistatic activity of fluconazole against these strains (Fig. 2B).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Azole resistance mechanisms have been studied most extensively in C. albicans and include alteration or overexpression of the target, activation or increased expression of azole efflux mediators, and induction of cellular stress responses (7).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [7] Robbins N, Caplan T, Cowen LE 2017 Molecular evolution of antifungal drug resistance. Annu Rev Microbiol 71: 753– 775. doi: 10.1146/annurev-micro-030117-020345. 28886681 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The most widely deployed class of antifungal is the azoles, which inhibit fungal growth by targeting lanosterol 14-α-demethylase (Erg11), a key component of the pathway for biosynthesis of the membrane sterol ergosterol (7).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [7] Robbins N, Caplan T, Cowen LE 2017 Molecular evolution of antifungal drug resistance. Annu Rev Microbiol 71: 753– 775. doi: 10.1146/annurev-micro-030117-020345. 28886681 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Specifically, in C. albicans, the molecular chaperone Hsp90 promotes the evolution of drug resistance by stabilizing regulators of cellular responses to drug-induced stress (8).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [8] Cowen LE, Lindquist S 2005 Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309: 2185– 2189. doi: 10.1126/science.1118370. 16195452 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hsp90 represses filamentous growth in C. albicans such that compromising Hsp90 function induces the yeast-to-filament transition by relieving repression on Ras1-protein kinase A (PKA) signaling (19).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [19] Shapiro RS, Uppuluri P, Zaas AK, Collins C, Senn H, Perfect JR, Heitman J, Cowen LE 2009 Hsp90 orchestrates temperature-dependent Candida albicans morphogenesis via Ras1-PKA signaling. Curr Biol 19: 621– 629. doi: 10.1016/j.cub.2009.03.017. 19327993 PMC2735497 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Inhibition of Hsp90 blocks calcineurin-dependent stress responses and cell wall integrity signaling, thereby reducing antifungal tolerance of clinical isolates and transforming azole activity from fungistatic to fungicidal (8–11).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [8] Cowen LE, Lindquist S 2005 Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309: 2185– 2189. doi: 10.1126/science.1118370. 16195452 source
- Not checked yetcites [9] LaFayette SL, Collins C, Zaas AK, Schell WA, Betancourt-Quiroz M, Gunatilaka AAL, Perfect JR, Cowen LE 2010 PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90. PLoS Pathog 6: e1001069. doi: 10.1371/journal.ppat.1001069. 20865172 PMC2928802 source
- Not checked yetcites [10] Singh SD, Robbins N, Zaas AK, Schell WA, Perfect JR, Cowen LE 2009 Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog 5: e1000532. doi: 10.1371/journal.ppat.1000532. 19649312 PMC2712069 source
- Not checked yetcites [11] Caplan T, Polvi EJ, Xie JL, Buckhalter S, Leach MD, Robbins N, Cowen LE 2018 Functional genomic screening reveals core modulators of echinocandin stress responses in Candida albicans. Cell Rep 23: 2292– 2298. doi: 10.1016/j.celrep.2018.04.084. 29791841 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The ability of C. albicans to transition between yeast and filamentous forms is a key virulence trait that is triggered by a wide variety of environmental cues (20).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [20] Shapiro RS, Robbins N, Cowen LE 2011 Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiol Mol Biol Rev 75: 213– 267. doi: 10.1128/MMBR.00045-10. 21646428 PMC3122626 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In C. auris, studies have suggested that point mutations in ERG11 contribute to azole resistance of clinical isolates (15).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [15] Healey KR, Kordalewska M, Jiménez Ortigosa C, Singh A, Berrío I, Chowdhary A, Perlin DS 2018 Limited ERG11 mutations identified in isolates of Candida auris directly contribute to reduced azole susceptibility. Antimicrob Agents Chemother 62: e01427-18. doi: 10.1128/AAC.01427-18. PMC6153782 30082281 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Moreover, the impact of Hsp90 on drug resistance has been conserved in a number of other fungal pathogens, including Candida glabrata and Aspergillus fumigatus (12–14).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [12] Cowen LE, Singh SD, Köhler JR, Collins C, Zaas AK, Schell WA, Aziz H, Mylonakis E, Perfect JR, Whitesell L, Lindquist S 2009 Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. Proc Natl Acad Sci U S A 106: 2818– 2823. doi: 10.1073/pnas.0813394106. 19196973 PMC2650349 source
- Not checked yetcites [13] Singh-Babak SD, Babak T, Diezmann S, Hill JA, Xie JL, Chen Y-LL, Poutanen SM, Rennie RP, Heitman J, Cowen LE 2012 Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata. PLoS Pathog 8: e1002718. doi: 10.1371/journal.ppat.1002718. 22615574 PMC3355103 source
- Not checked yetcites [14] Lamoth F, Juvvadi PR, Gehrke C, Steinbach WJ 2013 In vitro activity of calcineurin and heat shock protein 90 inhibitors against Aspergillus fumigatus azole- and echinocandin-resistant strains. Antimicrob Agents Chemother 57: 1035– 1039. doi: 10.1128/AAC.01857-12. 23165466 PMC3553695 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In addition to its role in enabling the emergence and maintenance of azole resistance, Hsp90 governs temperature-dependent morphogenesis in C. albicans (19).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [19] Shapiro RS, Uppuluri P, Zaas AK, Collins C, Senn H, Perfect JR, Heitman J, Cowen LE 2009 Hsp90 orchestrates temperature-dependent Candida albicans morphogenesis via Ras1-PKA signaling. Curr Biol 19: 621– 629. doi: 10.1016/j.cub.2009.03.017. 19327993 PMC2735497 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“However, exposure to various cues that induce C. albicans filamentation does not induce morphogenesis in C. auris, suggesting divergence in the circuitry governing the yeast-to-filament transition between the two Candida species (23).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > INTRODUCTION
What the sources say
- Not checked yetcites [23] Larkin E, Hager C, Chandra J, Mukherjee PK, Retuerto M, Salem I, Long L, Isham N, Kovanda L, Borroto-Esoda K, Wring S, Angulo D, Ghannoum M 2017 The emerging pathogen Candida auris: growth phenotype, virulence factors, activity of antifungals, and effect of SCY-078, a novel glucan synthesis inhibitor, on growth morphology and biofilm formation. Antimicrob Agents Chemother 61: e02396-16. doi: 10.1128/AAC.02396-16. 28223375 PMC5404565 source
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“The fluconazole-potentiating effect of Hsp90 inhibition is reminiscent of the results of a study of a series of C. albicans clinical isolates from an AIDS patient, with the early clinical isolates showing an Hsp90-dependent fluconazole tolerance phenotype (8, 27, 28).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [8] Cowen LE, Lindquist S 2005 Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309: 2185– 2189. doi: 10.1126/science.1118370. 16195452 source
- Not checked yetcites [27] White TC 1997 Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. Antimicrob Agents Chemother 41: 1482– 1487. 9210670 PMC163944 source
- Not checked yetcites [28] Hill JA, O’Meara TR, Cowen LE 2015 Fitness trade-offs associated with the evolution of resistance to antifungal drug combinations. Cell Rep 10: 809– 819. doi: 10.1016/j.celrep.2015.01.009. 25660029 source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Only one study has reported filamentous growth in C. auris to date, and that growth occurred under conditions of high salt concentrations (31).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [31] Wang X, Bing J, Zheng Q, Zhang F, Liu J, Yue H, Tao L, Du H, Wang Y, Wang H, Huang G 2018 The first isolate of Candida auris in China: clinical and biological aspects. Emerg Microbes Infect 7: 93. doi: 10.1038/s41426-018-0095-0. 29777096 PMC5959928 source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Over time, these isolates showed stepwise increases in fluconazole resistance that became independent of Hsp90 as the isolates acquired mutations in ERG11 and in the transcriptional activator of CDR1, TAC1 (8, 27, 28).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [8] Cowen LE, Lindquist S 2005 Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309: 2185– 2189. doi: 10.1126/science.1118370. 16195452 source
- Not checked yetcites [27] White TC 1997 Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. Antimicrob Agents Chemother 41: 1482– 1487. 9210670 PMC163944 source
- Not checked yetcites [28] Hill JA, O’Meara TR, Cowen LE 2015 Fitness trade-offs associated with the evolution of resistance to antifungal drug combinations. Cell Rep 10: 809– 819. doi: 10.1016/j.celrep.2015.01.009. 25660029 source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Although universal changes in cell surface composition upon morphogenesis have not been identified in fungi, cell surface proteins are often important regulators of morphogenesis and many are required for flocculation and adhesion, which are phenotypes associated with specific morphogenetic states (43).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [43] Gow NAR, Latge J-P, Munro CA 2017 The fungal cell wall: structure, biosynthesis, and function. Microbiol Spectr 5. doi: 10.1128/microbiolspec.FUNK-0035-2016. PMC11687499 28513415 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our use of the tetracycline-repressible promoter system to regulate the expression of HSP90 in C. auris establishes a precedent for genetic analysis of essential genes in this pathogen.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although morphogenesis is an important virulence trait in C. albicans and other fungal pathogens (40), the role of filamentous growth in C. auris is unclear.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [40] Gow NAR, Brown AJP, Odds FC 2002 Fungal morphogenesis and host invasion. Curr Opin Microbiol 5: 366– 371. 12160854 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This analysis validates the idea that a core transcriptional response accompanies C. albicans morphogenesis in response to perturbation of Hsp90 function and provides a powerful platform for comparative analyses with the transcriptional response in C. auris.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“In addition, antifungal exposure has been shown to elicit distinct transcriptional responses between C. albicans and C. auris, suggesting that distinct genes may contribute to antifungal resistance in C. auris (18).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [18] Muñoz JF, Gade L, Chow NA, Loparev VN, Juieng P, Berkow EL, Farrer RA, Litvintseva AP, Cuomo CA 2018 Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species. Nat Commun 9: 5346. 30559369 PMC6297351 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In C. albicans, filamentous growth is also associated with extensive cell surface remodeling as indicated by changes in cell surface components at the transcriptomic and proteomic levels (32).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
What the sources say
- Not checked yetcites [32] Nantel A, Dignard D, Bachewich C, Harcus D, Marcil A, Bouin A-PP, Sensen CW, Hogues H, van Het Hoog M, Gordon P, Rigby T, Benoit F, Tessier DC, Thomas DY, Whiteway M, Van Het HM, Gordon P, Rigby T, Benoit F, Tessier DC, Thomas DY, Whiteway M 2002 Transcription profiling of Candida albicans cells undergoing the yeast-to-hyphal transition. Mol Biol Cell 13: 3452– 3465. doi: 10.1091/mbc.e02-05-0272. 12388749 PMC129958 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the specific genes that are regulated during the morphogenetic transition are largely distinct between the two species, the regulation of cell surface-associated genes during filamentous growth appears to be conserved between C. auris and C. albicans.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This highlights that azole resistance in these strains is likely due to the poor engagement of fluconazole with its cellular target Erg11 and/or to the upregulation of azole efflux pumps, thereby minimizing drug-induced cellular stress.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The absence of nonsynonymous mutations in plasmids was verified by sequencing.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > MATERIALS AND METHODS > Plasmid construction.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“RNA was prepared in quadruplicate as described above.”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > MATERIALS AND METHODS > RNA sequencing.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Little is known about the mechanisms of azole resistance in C. auris, and genetic control of azole resistance in this organism has yet to be explored.
“However, the mechanisms governing drug resistance and virulence in this organism remain largely unexplored.”
“Despite the high incidence of azole resistance reported for C. auris isolates, little is known about the mechanisms involved.”
“Despite these initial reports, genetic control of azole resistance has yet to be explored in C. auris.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“including the Cdr1 multidrug efflux ATP-binding cassette (ABC) transporter, the Mdr1 major facilitator and the putative phosphatidylinositol transfer protein Pdr16 (ref. 18), all of which cause clinical azole resistance16,19,20.”
From Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103 (2025) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Moreover, some genes expressed in C. albicans hyphal phase have no orthologs in C. auris (e.g., ECE1, HWP1) or no significant change of expression in different conditions inducing C. auris filamentation (e.g., FLO8, EFG1, BRG1, BCR1, EFH1), suggesting distinct pathways between these genotypically distant Candida spp. (20, 37, 47).”
From Ume6-dependent pathways of morphogenesis and biofilm formation in Candida auris (2024) · cites this paper as [37]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“PHR1 was also upregulated following Hsp90 repression/inhibition, along with SCF1 and other genes of cell surface proteins exhibiting increased expression in UME6HA (PGA26, RBT4/KRE1) (37).”
From Ume6-dependent pathways of morphogenesis and biofilm formation in Candida auris (2024) · cites this paper as [37]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Together with other data sets containing genes upregulated in contact with blood cells [node “BLOOD_60 MIN_UP” (36)] and genes upregulated by deprivation of Hsp90 [node “HSP90_TET_UP”, (37)], these conditions have in common that they favor the filamentous phase of C. auris, which is consistent with the morphological effect of UME6HA on C. auris.”
From Ume6-dependent pathways of morphogenesis and biofilm formation in Candida auris (2024) · cites this paper as [37]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
“Three clinical isolates, CDC-381, CDC-382, and CDC-387, were more susceptible to fluconazole than the other strains. Of these, CDC-381 and CDC-382 showed a tolerance phenotype with persistent growth beyond the drug MIC (Fig. 2A).”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > Hsp90 is an important mediator of tolerance in C. auris.
“For strains CDC-382 and CDC-387, geldanamycin abrogated tolerance of fluconazole at concentrations above their fluconazole MICs (Fig. 2B)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > RESULTS > C. auris filamentation is associated with transcriptional induction of putative cell surface genes.
“PHR1 (B9J08_000918)”
§ Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance > DISCUSSION
“PHR1 (B9J08_003910)”
Citations
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“United States, with Candida albicans being the primary cause of candidiasis exhibiting mortality rates of 40%, even with current treatments (2, 3).”
Background
Cited by
Sorted by citations
Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond
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Self-citationCandida auris: Epidemiology, biology, antifungal resistance, and virulence
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Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium
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Self-citation
Metadata
- Authors
- Kim, S. H., Iyer, K. R., Pardeshi, L., Muñoz, J. F., Robbins, N., Cuomo, C. A., Wong, K. H., & Cowen, L. E.
- Affiliations
- University of Toronto (CA)
- University of Macau (MO)
- Broad Institute (US)
- Corresponding author
- Cowen, Leah E.
- ORCID
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2019-02-26
- Volume
- 10
- Issue
- 1
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC6355988
- OpenAlex
- W2912190166
- Semantic Scholar
- faa753073db5582ce1a9af26d79179b9584623e5
- Cited by
- 136
- References
- 53
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 18 · 2023: 17 · 2022: 18 · 2021: 21 · 2020: 25 · 2019: 9
- FWCI
- 13.98
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-03-19)
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (FDN154288, 119520_1, MOP-86452)
- National Institute of Allergy and Infectious Diseases (U19AI110818)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
- Keywords
- Candida auris, HSP90, azole resistance, yeast-to-hypha transition, morphogenesis, conditional gene expression, ergosterol biosynthesis, antifungal resistance, virulence, transcriptional remodeling, fungal pathogens
- MeSH terms
- Antifungal Agents, Azoles, Candida, Drug Tolerance, Gene Deletion, HSP90 Heat-Shock Proteins, Drug Resistance, Fungal, Membrane Transport Proteins, Gene Knockdown Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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