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

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

mBio, Volume: 9, Issue: 3, Start page: e00225-18

Swansea University Authors: Josie Parker, Steven Kelly Orcid Logo

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DOI (Published version): 10.1128/mBio.00225-18

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, an...

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Published in: mBio
ISSN: 2150-7511
Published: 2018
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URI: https://cronfa.swan.ac.uk/Record/cronfa40336
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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&#x394;/&#x394; mutant was unable to cause lethality in the disseminated model, it induced pathology in a mouse model of vaginal infection. The erg3&#x394;/&#x394; 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</abstract><type>Journal Article</type><journal>mBio</journal><volume>9</volume><journalNumber>3</journalNumber><paginationStart>e00225-18</paginationStart><publisher/><issnElectronic>2150-7511</issnElectronic><keywords/><publishedDay>22</publishedDay><publishedMonth>5</publishedMonth><publishedYear>2018</publishedYear><publishedDate>2018-05-22</publishedDate><doi>10.1128/mBio.00225-18</doi><url/><notes/><college>COLLEGE NANME</college><department>Medicine, Health and Life Science - Faculty</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>FGMHL</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2020-06-17T16:54:22.1428100</lastEdited><Created>2018-05-23T12:23:34.0277957</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Arturo</firstname><surname>Luna-Tapia</surname><order>1</order></author><author><firstname>Hubertine M. 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David</firstname><surname>Rogers</surname><order>7</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><orcid>0000-0001-7991-5040</orcid><order>8</order></author><author><firstname>Brian M.</firstname><surname>Peters</surname><order>9</order></author><author><firstname>Glen E.</firstname><surname>Palmer</surname><order>10</order></author></authors><documents><document><filename>0040336-13062018124611.pdf</filename><originalFilename>40336.pdf</originalFilename><uploaded>2018-06-13T12:46:11.8930000</uploaded><type>Output</type><contentLength>1955702</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><embargoDate>2018-06-13T00:00:00.0000000</embargoDate><documentNotes>This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2020-06-17T16:54:22.1428100 v2 40336 2018-05-23 Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2018-05-23 FGMHL 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 Journal Article mBio 9 3 e00225-18 2150-7511 22 5 2018 2018-05-22 10.1128/mBio.00225-18 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University 2020-06-17T16:54:22.1428100 2018-05-23T12:23:34.0277957 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Arturo Luna-Tapia 1 Hubertine M. E. Willems 2 Josie Parker 3 Hélène Tournu 4 Katherine S. Barker 5 Andrew T. Nishimoto 6 P. David Rogers 7 Steven Kelly 0000-0001-7991-5040 8 Brian M. Peters 9 Glen E. Palmer 10 0040336-13062018124611.pdf 40336.pdf 2018-06-13T12:46:11.8930000 Output 1955702 application/pdf Version of Record true 2018-06-13T00:00:00.0000000 This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. true eng
title Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity
spellingShingle Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity
Josie Parker
Steven Kelly
title_short Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity
title_full Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity
title_fullStr Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity
title_full_unstemmed Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity
title_sort Loss of Upc2p-Inducible ERG3 Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity
author_id_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Josie Parker
Steven Kelly
author2 Arturo Luna-Tapia
Hubertine M. E. Willems
Josie Parker
Hélène Tournu
Katherine S. Barker
Andrew T. Nishimoto
P. David Rogers
Steven Kelly
Brian M. Peters
Glen E. Palmer
format Journal article
container_title mBio
container_volume 9
container_issue 3
container_start_page e00225-18
publishDate 2018
institution Swansea University
issn 2150-7511
doi_str_mv 10.1128/mBio.00225-18
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description 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
published_date 2018-05-22T03:51:23Z
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