Deletion of the Stress Response Gene DDR48 from Histoplasma capsulatum Increases Sensitivity to Oxidative Stress, Increases Susceptibility to Antifungals, and Decreases Fitness in Macrophages

The stress response gene DDR48 has been characterized in Saccharomyces cerevisiae and Candida albicans to be involved in combating various cellular stressors, from oxidative agents to antifungal compounds. Surprisingly, the biological function...

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Autores principales:	Logan T. Blancett, Kauri A. Runge, Gabriella M. Reyes, Lauren A. Kennedy, Sydney C. Jackson, Sarah E. Scheuermann, Mallory B. Harmon, Jamease C. Williams, Glenmore Shearer
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>Histoplasma</i> <i>DDR48</i> paraquat hydrogen peroxide amphotericin-B ketoconazole Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/319bdb99667246979d08b0c8f711be40
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spelling	oai:doaj.org-article:319bdb99667246979d08b0c8f711be402021-11-25T18:06:29ZDeletion of the Stress Response Gene <i>DDR48</i> from <i>Histoplasma capsulatum</i> Increases Sensitivity to Oxidative Stress, Increases Susceptibility to Antifungals, and Decreases Fitness in Macrophages10.3390/jof71109812309-608Xhttps://doaj.org/article/319bdb99667246979d08b0c8f711be402021-11-01T00:00:00Zhttps://www.mdpi.com/2309-608X/7/11/981https://doaj.org/toc/2309-608XThe stress response gene <i>DDR48</i> has been characterized in <i>Saccharomyces cerevisiae</i> and <i>Candida albicans</i> to be involved in combating various cellular stressors, from oxidative agents to antifungal compounds. Surprisingly, the biological function of <i>DDR48</i> has yet to be identified, though it is likely an important part of the stress response. To gain insight into its function, we characterized <i>DDR48</i> in the dimorphic fungal pathogen <i>Histoplasma capsulatum</i>. Transcriptional analyses showed preferential expression of <i>DDR48</i> in the mycelial phase. Induction of <i>DDR48</i> in <i>Histoplasma</i> yeasts developed after treatment with various cellular stress compounds. We generated a <i>ddr48∆</i> deletion mutant to further characterize <i>DDR48</i> function. Loss of <i>DDR48</i> alters the transcriptional profile of the oxidative stress response and membrane synthesis pathways. Treatment with ROS or antifungal compounds reduced survival of <i>ddr48∆</i> yeasts compared to controls, consistent with an aberrant cellular stress response. In addition, we infected RAW 264.7 macrophages with <i>DDR48</i>-expressing and <i>ddr48∆</i> yeasts and observed a 50% decrease in recovery of <i>ddr48∆</i> yeasts compared to wild-type yeasts. Loss of <i>DDR48</i> function results in numerous negative effects in <i>Histoplasma</i> yeasts, highlighting its role as a key player in the global sensing and response to cellular stress by fungi.Logan T. BlancettKauri A. RungeGabriella M. ReyesLauren A. KennedySydney C. JacksonSarah E. ScheuermannMallory B. HarmonJamease C. WilliamsGlenmore ShearerMDPI AGarticle<i>Histoplasma</i><i>DDR48</i>paraquathydrogen peroxideamphotericin-BketoconazoleBiology (General)QH301-705.5ENJournal of Fungi, Vol 7, Iss 981, p 981 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>Histoplasma</i> <i>DDR48</i> paraquat hydrogen peroxide amphotericin-B ketoconazole Biology (General) QH301-705.5
spellingShingle	<i>Histoplasma</i> <i>DDR48</i> paraquat hydrogen peroxide amphotericin-B ketoconazole Biology (General) QH301-705.5 Logan T. Blancett Kauri A. Runge Gabriella M. Reyes Lauren A. Kennedy Sydney C. Jackson Sarah E. Scheuermann Mallory B. Harmon Jamease C. Williams Glenmore Shearer Deletion of the Stress Response Gene <i>DDR48</i> from <i>Histoplasma capsulatum</i> Increases Sensitivity to Oxidative Stress, Increases Susceptibility to Antifungals, and Decreases Fitness in Macrophages
description	The stress response gene <i>DDR48</i> has been characterized in <i>Saccharomyces cerevisiae</i> and <i>Candida albicans</i> to be involved in combating various cellular stressors, from oxidative agents to antifungal compounds. Surprisingly, the biological function of <i>DDR48</i> has yet to be identified, though it is likely an important part of the stress response. To gain insight into its function, we characterized <i>DDR48</i> in the dimorphic fungal pathogen <i>Histoplasma capsulatum</i>. Transcriptional analyses showed preferential expression of <i>DDR48</i> in the mycelial phase. Induction of <i>DDR48</i> in <i>Histoplasma</i> yeasts developed after treatment with various cellular stress compounds. We generated a <i>ddr48∆</i> deletion mutant to further characterize <i>DDR48</i> function. Loss of <i>DDR48</i> alters the transcriptional profile of the oxidative stress response and membrane synthesis pathways. Treatment with ROS or antifungal compounds reduced survival of <i>ddr48∆</i> yeasts compared to controls, consistent with an aberrant cellular stress response. In addition, we infected RAW 264.7 macrophages with <i>DDR48</i>-expressing and <i>ddr48∆</i> yeasts and observed a 50% decrease in recovery of <i>ddr48∆</i> yeasts compared to wild-type yeasts. Loss of <i>DDR48</i> function results in numerous negative effects in <i>Histoplasma</i> yeasts, highlighting its role as a key player in the global sensing and response to cellular stress by fungi.
format	article
author	Logan T. Blancett Kauri A. Runge Gabriella M. Reyes Lauren A. Kennedy Sydney C. Jackson Sarah E. Scheuermann Mallory B. Harmon Jamease C. Williams Glenmore Shearer
author_facet	Logan T. Blancett Kauri A. Runge Gabriella M. Reyes Lauren A. Kennedy Sydney C. Jackson Sarah E. Scheuermann Mallory B. Harmon Jamease C. Williams Glenmore Shearer
author_sort	Logan T. Blancett
title	Deletion of the Stress Response Gene <i>DDR48</i> from <i>Histoplasma capsulatum</i> Increases Sensitivity to Oxidative Stress, Increases Susceptibility to Antifungals, and Decreases Fitness in Macrophages
title_short	Deletion of the Stress Response Gene <i>DDR48</i> from <i>Histoplasma capsulatum</i> Increases Sensitivity to Oxidative Stress, Increases Susceptibility to Antifungals, and Decreases Fitness in Macrophages
title_full	Deletion of the Stress Response Gene <i>DDR48</i> from <i>Histoplasma capsulatum</i> Increases Sensitivity to Oxidative Stress, Increases Susceptibility to Antifungals, and Decreases Fitness in Macrophages
title_fullStr	Deletion of the Stress Response Gene <i>DDR48</i> from <i>Histoplasma capsulatum</i> Increases Sensitivity to Oxidative Stress, Increases Susceptibility to Antifungals, and Decreases Fitness in Macrophages
title_full_unstemmed	Deletion of the Stress Response Gene <i>DDR48</i> from <i>Histoplasma capsulatum</i> Increases Sensitivity to Oxidative Stress, Increases Susceptibility to Antifungals, and Decreases Fitness in Macrophages
title_sort	deletion of the stress response gene <i>ddr48</i> from <i>histoplasma capsulatum</i> increases sensitivity to oxidative stress, increases susceptibility to antifungals, and decreases fitness in macrophages
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/319bdb99667246979d08b0c8f711be40
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Deletion of the Stress Response Gene <i>DDR48</i> from <i>Histoplasma capsulatum</i> Increases Sensitivity to Oxidative Stress, Increases Susceptibility to Antifungals, and Decreases Fitness in Macrophages

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