Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in <named-content content-type="genus-species">Candida albicans</named-content>

ABSTRACT How cells exposed to one stress are later able to better survive other types of stress is not well understood. In eukaryotic organisms, physiological and pathological stresses can disturb endoplasmic reticulum (ER) function, resulting in “ER stress.” Here, we found that exposure to tunicamy...

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Autores principales:	Feng Yang, Vladimir Gritsenko, Yaniv Slor Futterman, Lu Gao, Cheng Zhen, Hui Lu, Yuan-ying Jiang, Judith Berman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	antifungal tolerance cross-adaptation stress response trisomy Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/049ece0840e44c8792496e6c6d300248
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spelling	oai:doaj.org-article:049ece0840e44c8792496e6c6d3002482021-11-10T18:37:52ZTunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in <named-content content-type="genus-species">Candida albicans</named-content>10.1128/mBio.02272-212150-7511https://doaj.org/article/049ece0840e44c8792496e6c6d3002482021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02272-21https://doaj.org/toc/2150-7511ABSTRACT How cells exposed to one stress are later able to better survive other types of stress is not well understood. In eukaryotic organisms, physiological and pathological stresses can disturb endoplasmic reticulum (ER) function, resulting in “ER stress.” Here, we found that exposure to tunicamycin, an inducer of ER stress, resulted in the acquisition of a specific aneuploidy, chromosome 2 trisomy (Chr2x3), in Candida albicans. Importantly, the resulting aneuploidy also conferred cross-tolerance to caspofungin, a first-line echinocandin antifungal, as well as to hydroxyurea, a common chemotherapeutic agent. Exposure to a range of tunicamycin concentrations induced similar ER stress responses. Extra copies of one Chr2 gene, MKK2, affected both tunicamycin and caspofungin tolerance, while at least 3 genes on chromosome 2 (ALG7, RTA2, and RTA3) affected only tunicamycin and not caspofungin responses. Other Chr2 genes (RNR1 and RNR21) affected hydroxyurea tolerance but neither tunicamycin nor caspofungin tolerance. Deletion of components of the protein kinase C (PKC) or calcineurin pathways affected tolerance to both tunicamycin and caspofungin, supporting the idea that the ER stress response and echinocandin tolerance are regulated by overlapping stress response pathways. Thus, antifungal drug tolerance can arise rapidly via ER stress-induced aneuploidy. IMPORTANCE Candida albicans is a prevalent human fungal commensal and also a pathogen that causes life-threatening systemic infections. Treatment failures are frequent because few therapeutic antifungal drug classes are available and because drug resistance and tolerance limit drug efficacy. We found that C. albicans rapidly overcomes the cellular stress induced by the drug tunicamycin by duplicating chromosome 2. Also, chromosome 2 duplication confers tolerance not only to tunicamycin but also to the following two unrelated drugs: caspofungin, an antifungal drug, and hydroxyurea, a chemotherapeutic. Cross tolerance to the three drugs involves different sets of genes, although some genetic pathways affect the tolerance to two of these three drugs. This work highlights a serious concern, namely, that changes in whole chromosome copy number can occur in response to one type of stress, and yet, they may facilitate the emergence of tolerance to multiple drugs, including the few antifungal drug classes available to treat Candida infections.Feng YangVladimir GritsenkoYaniv Slor FuttermanLu GaoCheng ZhenHui LuYuan-ying JiangJudith BermanAmerican Society for Microbiologyarticleantifungal tolerancecross-adaptationstress responsetrisomyMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antifungal tolerance cross-adaptation stress response trisomy Microbiology QR1-502
spellingShingle	antifungal tolerance cross-adaptation stress response trisomy Microbiology QR1-502 Feng Yang Vladimir Gritsenko Yaniv Slor Futterman Lu Gao Cheng Zhen Hui Lu Yuan-ying Jiang Judith Berman Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in <named-content content-type="genus-species">Candida albicans</named-content>
description	ABSTRACT How cells exposed to one stress are later able to better survive other types of stress is not well understood. In eukaryotic organisms, physiological and pathological stresses can disturb endoplasmic reticulum (ER) function, resulting in “ER stress.” Here, we found that exposure to tunicamycin, an inducer of ER stress, resulted in the acquisition of a specific aneuploidy, chromosome 2 trisomy (Chr2x3), in Candida albicans. Importantly, the resulting aneuploidy also conferred cross-tolerance to caspofungin, a first-line echinocandin antifungal, as well as to hydroxyurea, a common chemotherapeutic agent. Exposure to a range of tunicamycin concentrations induced similar ER stress responses. Extra copies of one Chr2 gene, MKK2, affected both tunicamycin and caspofungin tolerance, while at least 3 genes on chromosome 2 (ALG7, RTA2, and RTA3) affected only tunicamycin and not caspofungin responses. Other Chr2 genes (RNR1 and RNR21) affected hydroxyurea tolerance but neither tunicamycin nor caspofungin tolerance. Deletion of components of the protein kinase C (PKC) or calcineurin pathways affected tolerance to both tunicamycin and caspofungin, supporting the idea that the ER stress response and echinocandin tolerance are regulated by overlapping stress response pathways. Thus, antifungal drug tolerance can arise rapidly via ER stress-induced aneuploidy. IMPORTANCE Candida albicans is a prevalent human fungal commensal and also a pathogen that causes life-threatening systemic infections. Treatment failures are frequent because few therapeutic antifungal drug classes are available and because drug resistance and tolerance limit drug efficacy. We found that C. albicans rapidly overcomes the cellular stress induced by the drug tunicamycin by duplicating chromosome 2. Also, chromosome 2 duplication confers tolerance not only to tunicamycin but also to the following two unrelated drugs: caspofungin, an antifungal drug, and hydroxyurea, a chemotherapeutic. Cross tolerance to the three drugs involves different sets of genes, although some genetic pathways affect the tolerance to two of these three drugs. This work highlights a serious concern, namely, that changes in whole chromosome copy number can occur in response to one type of stress, and yet, they may facilitate the emergence of tolerance to multiple drugs, including the few antifungal drug classes available to treat Candida infections.
format	article
author	Feng Yang Vladimir Gritsenko Yaniv Slor Futterman Lu Gao Cheng Zhen Hui Lu Yuan-ying Jiang Judith Berman
author_facet	Feng Yang Vladimir Gritsenko Yaniv Slor Futterman Lu Gao Cheng Zhen Hui Lu Yuan-ying Jiang Judith Berman
author_sort	Feng Yang
title	Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in <named-content content-type="genus-species">Candida albicans</named-content>
title_short	Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in <named-content content-type="genus-species">Candida albicans</named-content>
title_full	Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in <named-content content-type="genus-species">Candida albicans</named-content>
title_fullStr	Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in <named-content content-type="genus-species">Candida albicans</named-content>
title_full_unstemmed	Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in <named-content content-type="genus-species">Candida albicans</named-content>
title_sort	tunicamycin potentiates antifungal drug tolerance via aneuploidy in <named-content content-type="genus-species">candida albicans</named-content>
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/049ece0840e44c8792496e6c6d300248
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Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in <named-content content-type="genus-species">Candida albicans</named-content>

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