Precise Expression of <italic toggle="yes">Afmed15</italic> Is Crucial for Asexual Development, Virulence, and Survival of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

ABSTRACT The rise of drug resistance in fungal pathogens is becoming a serious problem owing to the limited number of antifungal drugs available. Identifying and targeting factors essential for virulence or development unique to fungal pathogens is one approach to develop novel treatments for fungal...

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Autores principales:	Luyu Guan, Ruiyang Lu, Zhengjun Wu, Guowei Zhong, Shizhu Zhang
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Aspergillus fumigatus conidiation fungal cell death drug targets inducible gene expression opportunistic pathogen Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/99ceb123ce674f7ca846d1a424639417
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spelling	oai:doaj.org-article:99ceb123ce674f7ca846d1a4246394172021-11-15T15:30:59ZPrecise Expression of <italic toggle="yes">Afmed15</italic> Is Crucial for Asexual Development, Virulence, and Survival of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>10.1128/mSphere.00771-202379-5042https://doaj.org/article/99ceb123ce674f7ca846d1a4246394172020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00771-20https://doaj.org/toc/2379-5042ABSTRACT The rise of drug resistance in fungal pathogens is becoming a serious problem owing to the limited number of antifungal drugs available. Identifying and targeting factors essential for virulence or development unique to fungal pathogens is one approach to develop novel treatments for fungal infections. In this study, we present the identification and functional characterization of a novel developmental regulator in Aspergillus fumigatus, AfMed15, which contained a conserved Med15_fungal domain, as determined by screening of a mutant library that contained more than 2,000 hygromycin-resistant A. fumigatus transformants. Downregulating the expression of Afmed15 abolished the conidiation and decreased the fungal virulence in an insect model. Strikingly, the overexpression of Afmed15 caused fungal death accompanied by intensive autophagy. RNA sequencing of an Afmed15 overexpression strain revealed that altered gene expression patterns were associated with carbon metabolism, energy metabolism, and translation. Interestingly, the addition of metal ions could partially rescue fungal death caused by the overexpression of Afmed15, indicating that disordered ion homeostasis is a potential reason for the fungal death caused by the overexpression of Afmed15. Considering that the precise expression of Afmed15 is crucial for fungal development, virulence, and survival and that no ortholog was found in humans, Afmed15 is an ideal target for antifungal-drug development. IMPORTANCE The identification and characterization of regulators essential for virulence or development constitute one approach for antifungal drug development. In this study, we screened and functionally characterized Afmed15, a novel developmental regulator in A. fumigatus. We demonstrate that the precise transcriptional expression of Afmed15 is crucial for fungal asexual development, virulence, and survival. Downregulating the expression of Afmed15 abolished the conidiation and decreased the fungal virulence in an insect model. In contrast, the overexpression of Afmed15 caused fungal death accompanied by intensive autophagy. Our study provides a foundation for further studies to identify compounds perturbing the expression of Afmed15 that may be used for the prevention of invasive A. fumigatus infections.Luyu GuanRuiyang LuZhengjun WuGuowei ZhongShizhu ZhangAmerican Society for MicrobiologyarticleAspergillus fumigatusconidiationfungal cell deathdrug targetsinducible gene expressionopportunistic pathogenMicrobiologyQR1-502ENmSphere, Vol 5, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus conidiation fungal cell death drug targets inducible gene expression opportunistic pathogen Microbiology QR1-502
spellingShingle	Aspergillus fumigatus conidiation fungal cell death drug targets inducible gene expression opportunistic pathogen Microbiology QR1-502 Luyu Guan Ruiyang Lu Zhengjun Wu Guowei Zhong Shizhu Zhang Precise Expression of <italic toggle="yes">Afmed15</italic> Is Crucial for Asexual Development, Virulence, and Survival of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
description	ABSTRACT The rise of drug resistance in fungal pathogens is becoming a serious problem owing to the limited number of antifungal drugs available. Identifying and targeting factors essential for virulence or development unique to fungal pathogens is one approach to develop novel treatments for fungal infections. In this study, we present the identification and functional characterization of a novel developmental regulator in Aspergillus fumigatus, AfMed15, which contained a conserved Med15_fungal domain, as determined by screening of a mutant library that contained more than 2,000 hygromycin-resistant A. fumigatus transformants. Downregulating the expression of Afmed15 abolished the conidiation and decreased the fungal virulence in an insect model. Strikingly, the overexpression of Afmed15 caused fungal death accompanied by intensive autophagy. RNA sequencing of an Afmed15 overexpression strain revealed that altered gene expression patterns were associated with carbon metabolism, energy metabolism, and translation. Interestingly, the addition of metal ions could partially rescue fungal death caused by the overexpression of Afmed15, indicating that disordered ion homeostasis is a potential reason for the fungal death caused by the overexpression of Afmed15. Considering that the precise expression of Afmed15 is crucial for fungal development, virulence, and survival and that no ortholog was found in humans, Afmed15 is an ideal target for antifungal-drug development. IMPORTANCE The identification and characterization of regulators essential for virulence or development constitute one approach for antifungal drug development. In this study, we screened and functionally characterized Afmed15, a novel developmental regulator in A. fumigatus. We demonstrate that the precise transcriptional expression of Afmed15 is crucial for fungal asexual development, virulence, and survival. Downregulating the expression of Afmed15 abolished the conidiation and decreased the fungal virulence in an insect model. In contrast, the overexpression of Afmed15 caused fungal death accompanied by intensive autophagy. Our study provides a foundation for further studies to identify compounds perturbing the expression of Afmed15 that may be used for the prevention of invasive A. fumigatus infections.
format	article
author	Luyu Guan Ruiyang Lu Zhengjun Wu Guowei Zhong Shizhu Zhang
author_facet	Luyu Guan Ruiyang Lu Zhengjun Wu Guowei Zhong Shizhu Zhang
author_sort	Luyu Guan
title	Precise Expression of <italic toggle="yes">Afmed15</italic> Is Crucial for Asexual Development, Virulence, and Survival of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_short	Precise Expression of <italic toggle="yes">Afmed15</italic> Is Crucial for Asexual Development, Virulence, and Survival of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full	Precise Expression of <italic toggle="yes">Afmed15</italic> Is Crucial for Asexual Development, Virulence, and Survival of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_fullStr	Precise Expression of <italic toggle="yes">Afmed15</italic> Is Crucial for Asexual Development, Virulence, and Survival of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full_unstemmed	Precise Expression of <italic toggle="yes">Afmed15</italic> Is Crucial for Asexual Development, Virulence, and Survival of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_sort	precise expression of <italic toggle="yes">afmed15</italic> is crucial for asexual development, virulence, and survival of <named-content content-type="genus-species">aspergillus fumigatus</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/99ceb123ce674f7ca846d1a424639417
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Precise Expression of <italic toggle="yes">Afmed15</italic> Is Crucial for Asexual Development, Virulence, and Survival of <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

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