Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity

Luna-Tapia, Arturo; Willems, Hubertine M. E.; Parker, Josie E.; Tournu, Hélène; Barker, Katherine S.; Nishimoto, Andrew T.; Rogers, P. David; Kelly, Steven L.; Peters, Brian M.; Palmer, Glen E.

doi:10.1128/mbio.00225-18

Cited by 29Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity

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Luna-Tapia, Arturo, Willems, Hubertine M. E., Parker, Josie E., Tournu, Hélène, Barker, Katherine S., Nishimoto, Andrew T., Rogers, P. David, Kelly, Steven L. +2 more·2018·mBio

DOI 10.1128/mbio.00225-18PMC PMC5964354

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Abstract

ABSTRACT Inactivation of sterol Δ 5,6 -desaturase (Erg3p) in the prevalent fungal pathogen Candida albicans is one of several mechanisms that can confer resistance to the azole antifungal drugs. However, loss of Erg3p activity is also associated with deficiencies in stress tolerance, invasive hyphal growth, and attenuated virulence in a mouse model of disseminated infection. This may explain why relatively few erg3 -deficient strains have been reported among azole-resistant clinical isolates. In this study, we examined the consequences of Erg3p inactivation upon C. albicans pathogenicity and azole susceptibility in mouse models of mucosal and disseminated infection. While a C. albicans erg3 Δ/Δ mutant was unable to cause lethality in the disseminated model, it induced pathology in a mouse model of vaginal infection. The erg3 Δ/Δ mutant was also more resistant to fluconazole treatment than the wild type in both models of infection. Thus, complete loss of Erg3p activity confers azole resistance but also niche-specific virulence deficiencies. Serendipitously, we discovered that loss of azole-inducible ERG3 transcription (rather than complete inactivation) is sufficient to confer in vitro fluconazole resistance, without compromising C. albicans stress tolerance, hyphal growth, or pathogenicity in either mouse model. It is also sufficient to confer fluconazole resistance in the mouse vaginal model, but not in the disseminated model of infection, and thus confers niche-specific azole resistance without compromising C. albicans pathogenicity at either site. Collectively, these results establish that modulating Erg3p expression or activity can have niche-specific consequences on both C. albicans pathogenicity and azole resistance. IMPORTANCE While conferring resistance to the azole antifungals in vitro , loss of sterol Δ 5,6 -desaturase (Erg3p) activity has also been shown to reduce C. albicans pathogenicity. Accordingly, it has been presumed that this mechanism may not be significant in the clinical setting. The results presented here challenge this assumption, revealing a more complex relationship between Erg3p activity, azole resistance, C. albicans pathogenicity, and the specific site of infection. Most importantly, we have shown that even modest changes in ERG3 transcription are sufficient to confer azole resistance without compromising C. albicans fitness or pathogenicity. Given that previous efforts to assess the importance of ERG3 as a determinant of clinical azole resistance have focused almost exclusively on detecting null mutants, its role may have been grossly underestimated. On the basis of our results, a more thorough investigation of the contribution of the ERG3 gene to azole resistance in the clinical setting is warranted.

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Changes within the ERG3 promoter that affect expression and activity may be sufficient to confer azole resistance in niche-specific instances without affecting C. albicans pathogenicity.
“changes within the ERG3 promoter that affect expression and activity may be sufficient to confer azole resistance in niche-specific instances without affecting C. albicans pathogenicity”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [149]

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Authors: Luna-Tapia, A., Willems, H. M. E., Parker, J. E., Tournu, H., Barker, K. S., Nishimoto, A. T., Rogers, P. D., Kelly, S. L., Peters, B. M., & Palmer, G. E.
Affiliations: University of Tennessee Health Science Center (US)
Swansea University (GB)
Corresponding author: Palmer, Glen E.
ORCID: Willems, Hubertine M. E.
Parker, Josie E.
Barker, Katherine S.
Nishimoto, Andrew T.
Rogers, P. David
Kelly, Steven L.
Peters, Brian M.
Palmer, Glen E.
Venue: mBio
Publisher: American Society for Microbiology
Published: 2018-07-05
Volume: 9
Issue: 3
ISSN: 2150-7511 (ISSN-L)
2161-2129
DOI: 10.1128/mbio.00225-18
PMC: PMC5964354
OpenAlex: W2803110100
Cited by: 29
References: 58
Citations by year: 2026: 3 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 2
FWCI: 2.84
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
journals.asm.org/non-commercial-tdm-license (tdm)
Locations: mBio (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: HHS | NIH | National Institute of Allergy and Infectious Diseases (R01AI058145, R01AI099080, 5K22AI110541)
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 › Epidemiology › Fungal Infections and Studies
Keywords: Candida albicans, azole resistance, fluconazole resistance, fungal pathogenicity, systemic candidiasis, vaginal candidiasis, antifungal resistance, stress tolerance, hyphal growth, mouse infection model
MeSH terms: Animals, Antifungal Agents, Azoles, Candida albicans, Candidiasis, Female, Fungal Proteins, Humans, Mice, Inbred C57BL, Microbial Sensitivity Tests, Oxidoreductases, Virulence, Trans-Activators, Gene Expression Regulation, Fungal, Drug Resistance, Fungal, Mice

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Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity

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