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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-11-01
|
| Series: | Journal of Fungi |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2309-608X/7/11/981 |
| _version_ | 1797509770076225536 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:22:26Z |
| format | Article |
| id | doaj.art-319bdb99667246979d08b0c8f711be40 |
| institution | Directory Open Access Journal |
| issn | 2309-608X |
| language | English |
| last_indexed | 2024-03-10T05:22:26Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Fungi |
| spelling | doaj.art-319bdb99667246979d08b0c8f711be402023-11-22T23:56:35ZengMDPI AGJournal of Fungi2309-608X2021-11-0171198110.3390/jof7110981Deletion 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 MacrophagesLogan T. Blancett0Kauri A. Runge1Gabriella M. Reyes2Lauren A. Kennedy3Sydney C. Jackson4Sarah E. Scheuermann5Mallory B. Harmon6Jamease C. Williams7Glenmore Shearer8Center for Molecular and Cellular Biology, The University of Southern Mississippi, Hattiesburg, MS 39406, USACenter for Molecular and Cellular Biology, The University of Southern Mississippi, Hattiesburg, MS 39406, USACenter for Molecular and Cellular Biology, The University of Southern Mississippi, Hattiesburg, MS 39406, USACenter for Molecular and Cellular Biology, The University of Southern Mississippi, Hattiesburg, MS 39406, USACenter for Molecular and Cellular Biology, The University of Southern Mississippi, Hattiesburg, MS 39406, USACenter for Molecular and Cellular Biology, The University of Southern Mississippi, Hattiesburg, MS 39406, USACenter for Molecular and Cellular Biology, The University of Southern Mississippi, Hattiesburg, MS 39406, USACenter for Molecular and Cellular Biology, The University of Southern Mississippi, Hattiesburg, MS 39406, USACenter for Molecular and Cellular Biology, The University of Southern Mississippi, Hattiesburg, MS 39406, USAThe 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.https://www.mdpi.com/2309-608X/7/11/981<i>Histoplasma</i><i>DDR48</i>paraquathydrogen peroxideamphotericin-Bketoconazole |
| spellingShingle | 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 Journal of Fungi <i>Histoplasma</i> <i>DDR48</i> paraquat hydrogen peroxide amphotericin-B ketoconazole |
| 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_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_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_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 |
| topic | <i>Histoplasma</i> <i>DDR48</i> paraquat hydrogen peroxide amphotericin-B ketoconazole |
| url | https://www.mdpi.com/2309-608X/7/11/981 |
| work_keys_str_mv | AT logantblancett deletionofthestressresponsegeneiddr48ifromihistoplasmacapsulatumiincreasessensitivitytooxidativestressincreasessusceptibilitytoantifungalsanddecreasesfitnessinmacrophages AT kauriarunge deletionofthestressresponsegeneiddr48ifromihistoplasmacapsulatumiincreasessensitivitytooxidativestressincreasessusceptibilitytoantifungalsanddecreasesfitnessinmacrophages AT gabriellamreyes deletionofthestressresponsegeneiddr48ifromihistoplasmacapsulatumiincreasessensitivitytooxidativestressincreasessusceptibilitytoantifungalsanddecreasesfitnessinmacrophages AT laurenakennedy deletionofthestressresponsegeneiddr48ifromihistoplasmacapsulatumiincreasessensitivitytooxidativestressincreasessusceptibilitytoantifungalsanddecreasesfitnessinmacrophages AT sydneycjackson deletionofthestressresponsegeneiddr48ifromihistoplasmacapsulatumiincreasessensitivitytooxidativestressincreasessusceptibilitytoantifungalsanddecreasesfitnessinmacrophages AT sarahescheuermann deletionofthestressresponsegeneiddr48ifromihistoplasmacapsulatumiincreasessensitivitytooxidativestressincreasessusceptibilitytoantifungalsanddecreasesfitnessinmacrophages AT mallorybharmon deletionofthestressresponsegeneiddr48ifromihistoplasmacapsulatumiincreasessensitivitytooxidativestressincreasessusceptibilitytoantifungalsanddecreasesfitnessinmacrophages AT jameasecwilliams deletionofthestressresponsegeneiddr48ifromihistoplasmacapsulatumiincreasessensitivitytooxidativestressincreasessusceptibilitytoantifungalsanddecreasesfitnessinmacrophages AT glenmoreshearer deletionofthestressresponsegeneiddr48ifromihistoplasmacapsulatumiincreasessensitivitytooxidativestressincreasessusceptibilitytoantifungalsanddecreasesfitnessinmacrophages |