Loss of Upc2p-Inducible <italic toggle="yes">ERG3</italic> Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising <named-content content-type="genus-species">Candida albicans</named-content> Pathogenicity

ABSTRACT Inactivation of sterol Δ5,6-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 g...

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Autores principales:	Arturo Luna-Tapia, Hubertine M. E. Willems, Josie E. Parker, Hélène Tournu, Katherine S. Barker, Andrew T. Nishimoto, P. David Rogers, Steven L. Kelly, Brian M. Peters, Glen E. Palmer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	azole resistance Candida albicans disseminated candidiasis ERG3 mouse models pathogenesis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e3a04b7a36c249fbbe3ef214803936ec
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spelling	oai:doaj.org-article:e3a04b7a36c249fbbe3ef214803936ec2021-11-15T16:00:25ZLoss of Upc2p-Inducible <italic toggle="yes">ERG3</italic> Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising <named-content content-type="genus-species">Candida albicans</named-content> Pathogenicity10.1128/mBio.00225-182150-7511https://doaj.org/article/e3a04b7a36c249fbbe3ef214803936ec2018-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00225-18https://doaj.org/toc/2150-7511ABSTRACT Inactivation of sterol Δ5,6-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 erg3Δ/Δ mutant was unable to cause lethality in the disseminated model, it induced pathology in a mouse model of vaginal infection. The erg3Δ/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 Δ5,6-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.Arturo Luna-TapiaHubertine M. E. WillemsJosie E. ParkerHélène TournuKatherine S. BarkerAndrew T. NishimotoP. David RogersSteven L. KellyBrian M. PetersGlen E. PalmerAmerican Society for Microbiologyarticleazole resistanceCandida albicansdisseminated candidiasisERG3mouse modelspathogenesisMicrobiologyQR1-502ENmBio, Vol 9, Iss 3 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	azole resistance Candida albicans disseminated candidiasis ERG3 mouse models pathogenesis Microbiology QR1-502
spellingShingle	azole resistance Candida albicans disseminated candidiasis ERG3 mouse models pathogenesis Microbiology QR1-502 Arturo Luna-Tapia Hubertine M. E. Willems Josie E. Parker Hélène Tournu Katherine S. Barker Andrew T. Nishimoto P. David Rogers Steven L. Kelly Brian M. Peters Glen E. Palmer Loss of Upc2p-Inducible <italic toggle="yes">ERG3</italic> Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising <named-content content-type="genus-species">Candida albicans</named-content> Pathogenicity
description	ABSTRACT Inactivation of sterol Δ5,6-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 erg3Δ/Δ mutant was unable to cause lethality in the disseminated model, it induced pathology in a mouse model of vaginal infection. The erg3Δ/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 Δ5,6-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.
format	article
author	Arturo Luna-Tapia Hubertine M. E. Willems Josie E. Parker Hélène Tournu Katherine S. Barker Andrew T. Nishimoto P. David Rogers Steven L. Kelly Brian M. Peters Glen E. Palmer
author_facet	Arturo Luna-Tapia Hubertine M. E. Willems Josie E. Parker Hélène Tournu Katherine S. Barker Andrew T. Nishimoto P. David Rogers Steven L. Kelly Brian M. Peters Glen E. Palmer
author_sort	Arturo Luna-Tapia
title	Loss of Upc2p-Inducible <italic toggle="yes">ERG3</italic> Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising <named-content content-type="genus-species">Candida albicans</named-content> Pathogenicity
title_short	Loss of Upc2p-Inducible <italic toggle="yes">ERG3</italic> Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising <named-content content-type="genus-species">Candida albicans</named-content> Pathogenicity
title_full	Loss of Upc2p-Inducible <italic toggle="yes">ERG3</italic> Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising <named-content content-type="genus-species">Candida albicans</named-content> Pathogenicity
title_fullStr	Loss of Upc2p-Inducible <italic toggle="yes">ERG3</italic> Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising <named-content content-type="genus-species">Candida albicans</named-content> Pathogenicity
title_full_unstemmed	Loss of Upc2p-Inducible <italic toggle="yes">ERG3</italic> Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising <named-content content-type="genus-species">Candida albicans</named-content> Pathogenicity
title_sort	loss of upc2p-inducible <italic toggle="yes">erg3</italic> transcription is sufficient to confer niche-specific azole resistance without compromising <named-content content-type="genus-species">candida albicans</named-content> pathogenicity
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/e3a04b7a36c249fbbe3ef214803936ec
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Loss of Upc2p-Inducible <italic toggle="yes">ERG3</italic> Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising <named-content content-type="genus-species">Candida albicans</named-content> Pathogenicity

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