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
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...
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| Autores principales: | , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/319bdb99667246979d08b0c8f711be40 |
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| Sumario: | 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. |
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