Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicans

• Published in: mSphere Vol. 9; no. 3; p. e0080423
• Main Authors: Henry, Manon, Khemiri, Inès, Tebbji, Faiza, Abu-Helu, Rasmi, Vincent, Antony T, Sellam, Adnane
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 26-03-2024
• Subjects: Antifungal activity; Antifungal Agents - pharmacology; antifungal stress; Azoles; Candida albicans; Drug development; Enzymes; fungal virulence; Glycosylation; Heavy metals; Homeostasis; Humans; Hyphae; Iron; Manganese; Manganese - metabolism; manganese homeostasis; Metabolism; Metals; Microbial Genetics; Micronutrients; Nramp protein; Oxidative stress; Pathogens; Protein folding; Proteins; Research Article; Toxicity; Transition metals; unfolded protein response; Variance analysis; Virulence; Yeast; Candida albicans; manganese homeostasis; antifungal stress; unfolded protein response; fungal virulence
• ISSN: 2379-5042; 2379-5042
• DOI: 10.1128/msphere.00804-23

Due 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
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
, a member of Mn Nramp transporters, confirmed its contribution to Mn uptake.
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.
Transition 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,
. 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.