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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.
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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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Figures
![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
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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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In the paper
“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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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.
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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.
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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
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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.
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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.
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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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“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.
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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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“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.
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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.
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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
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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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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
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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
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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
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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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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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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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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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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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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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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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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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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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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.
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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
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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]
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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)”
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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
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