Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicans
ABSTRACTDue to the scarcity of transition metals within the human host, fungal pathogens have evolved sophisticated mechanisms to uptake and utilize these micronutrients at the infection interface. While considerable attention was turned to iron and copper acquisition mechanisms and their importance...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2024-03-01
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| Series: | mSphere |
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| Online Access: | https://journals.asm.org/doi/10.1128/msphere.00804-23 |
| _version_ | 1797221991916240896 |
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| author | Manon Henry Inès Khemiri Faiza Tebbji Rasmi Abu-Helu Antony T. Vincent Adnane Sellam |
| author_facet | Manon Henry Inès Khemiri Faiza Tebbji Rasmi Abu-Helu Antony T. Vincent Adnane Sellam |
| author_sort | Manon Henry |
| collection | DOAJ |
| description | ABSTRACTDue to the scarcity of transition metals within the human host, fungal pathogens have evolved sophisticated mechanisms to uptake and utilize these micronutrients at the infection interface. While considerable attention was turned to iron and copper acquisition mechanisms and their importance in fungal fitness, less was done regarding either the role of manganese (Mn) in infectious processes or the cellular mechanism by which fungal cells achieve their Mn-homeostasis. Here, we undertook transcriptional profiling in the pathogenic fungus Candida albicans experiencing both Mn starvation and excess to capture biological processes that are modulated by this metal. We uncovered that Mn scarcity influences diverse processes associated with fungal fitness including invasion of host cells and antifungal sensitivity. We show that Mn levels influence the abundance of iron and zinc emphasizing the complex crosstalk between metals. The deletion of SMF12, a member of Mn Nramp transporters, confirmed its contribution to Mn uptake. smf12 was unable to form hyphae and damage host cells and exhibited sensitivity to azoles. We found that the unfolded protein response (UPR), likely activated by decreased glycosylation under Mn limitation, was required to recover growth when cells were shifted from an Mn-starved to an Mn-repleted medium. RNA-seq profiling of cells exposed to Mn excess revealed that UPR was also activated. Furthermore, the UPR signaling axis Ire1-Hac1 was required to bypass Mn toxicity. Collectively, this study underscores the importance of Mn homeostasis in fungal virulence and comprehensively provides a portrait of biological functions that are modulated by Mn in a fungal pathogen.IMPORTANCETransition metals such as manganese provide considerable functionality across biological systems as they are used as cofactors for many catalytic enzymes. The availability of manganese is very limited inside the human body. Consequently, pathogenic microbes have evolved sophisticated mechanisms to uptake this micronutrient inside the human host to sustain their growth and cause infections. Here, we undertook a comprehensive approach to understand how manganese availability impacts the biology of the prevalent fungal pathogen, Candida albicans. We uncovered that manganese homeostasis in this pathogen modulates different biological processes that are essential for host infection which underscores the value of targeting fungal manganese homeostasis for potential antifungal therapeutics development. |
| first_indexed | 2024-04-24T13:14:14Z |
| format | Article |
| id | doaj.art-b4868a1f8a6145768d7da0aaf479ae5b |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-04-24T13:14:14Z |
| publishDate | 2024-03-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-b4868a1f8a6145768d7da0aaf479ae5b2024-04-05T01:32:10ZengAmerican Society for MicrobiologymSphere2379-50422024-03-019310.1128/msphere.00804-23Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicansManon Henry0Inès Khemiri1Faiza Tebbji2Rasmi Abu-Helu3Antony T. Vincent4Adnane Sellam5Montreal Heart Institute/Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec, CanadaMontreal Heart Institute/Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec, CanadaMontreal Heart Institute/Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec, CanadaDepartment of Medical Laboratory Sciences, Faculty of Health Professions, Al-Quds University, Jerusalem, PalestineDepartment of Animal Sciences, Université Laval, Quebec City, Québec, CanadaMontreal Heart Institute/Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec, CanadaABSTRACTDue to the scarcity of transition metals within the human host, fungal pathogens have evolved sophisticated mechanisms to uptake and utilize these micronutrients at the infection interface. While considerable attention was turned to iron and copper acquisition mechanisms and their importance in fungal fitness, less was done regarding either the role of manganese (Mn) in infectious processes or the cellular mechanism by which fungal cells achieve their Mn-homeostasis. Here, we undertook transcriptional profiling in the pathogenic fungus Candida albicans experiencing both Mn starvation and excess to capture biological processes that are modulated by this metal. We uncovered that Mn scarcity influences diverse processes associated with fungal fitness including invasion of host cells and antifungal sensitivity. We show that Mn levels influence the abundance of iron and zinc emphasizing the complex crosstalk between metals. The deletion of SMF12, a member of Mn Nramp transporters, confirmed its contribution to Mn uptake. smf12 was unable to form hyphae and damage host cells and exhibited sensitivity to azoles. We found that the unfolded protein response (UPR), likely activated by decreased glycosylation under Mn limitation, was required to recover growth when cells were shifted from an Mn-starved to an Mn-repleted medium. RNA-seq profiling of cells exposed to Mn excess revealed that UPR was also activated. Furthermore, the UPR signaling axis Ire1-Hac1 was required to bypass Mn toxicity. Collectively, this study underscores the importance of Mn homeostasis in fungal virulence and comprehensively provides a portrait of biological functions that are modulated by Mn in a fungal pathogen.IMPORTANCETransition metals such as manganese provide considerable functionality across biological systems as they are used as cofactors for many catalytic enzymes. The availability of manganese is very limited inside the human body. Consequently, pathogenic microbes have evolved sophisticated mechanisms to uptake this micronutrient inside the human host to sustain their growth and cause infections. Here, we undertook a comprehensive approach to understand how manganese availability impacts the biology of the prevalent fungal pathogen, Candida albicans. We uncovered that manganese homeostasis in this pathogen modulates different biological processes that are essential for host infection which underscores the value of targeting fungal manganese homeostasis for potential antifungal therapeutics development.https://journals.asm.org/doi/10.1128/msphere.00804-23Candida albicansmanganese homeostasisunfolded protein responseantifungal stressfungal virulence |
| spellingShingle | Manon Henry Inès Khemiri Faiza Tebbji Rasmi Abu-Helu Antony T. Vincent Adnane Sellam Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicans mSphere Candida albicans manganese homeostasis unfolded protein response antifungal stress fungal virulence |
| title | Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicans |
| title_full | Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicans |
| title_fullStr | Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicans |
| title_full_unstemmed | Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicans |
| title_short | Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicans |
| title_sort | manganese homeostasis modulates fungal virulence and stress tolerance in candida albicans |
| topic | Candida albicans manganese homeostasis unfolded protein response antifungal stress fungal virulence |
| url | https://journals.asm.org/doi/10.1128/msphere.00804-23 |
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