Dataset Information

Glucose Homeostasis Is Important for Immune Cell Viability during Candida Challenge and Host Survival of Systemic Fungal Infection.

ABSTRACT: To fight infections, macrophages undergo a metabolic shift whereby increased glycolysis fuels antimicrobial inflammation and killing of pathogens. Here we demonstrate that the pathogen Candida albicans turns this metabolic reprogramming into an Achilles' heel for macrophages. During Candida-macrophage interactions intertwined metabolic shifts occur, with concomitant upregulation of glycolysis in both host and pathogen setting up glucose competition. Candida thrives on multiple carbon sources, but infected macrophages are metabolically trapped in glycolysis and depend on glucose for viability: Candida exploits this limitation by depleting glucose, triggering rapid macrophage death. Using pharmacological or genetic means to modulate glucose metabolism of host and/or pathogen, we show that Candida infection perturbs host glucose homeostasis in the murine candidemia model and demonstrate that glucose supplementation improves host outcomes. Our results support the importance of maintaining glucose homeostasis for immune cell survival during Candida challenge and for host survival in systemic infection.

SUBMITTER: Tucey TM

PROVIDER: S-EPMC6709535 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Glucose Homeostasis Is Important for Immune Cell Viability during Candida Challenge and Host Survival of Systemic Fungal Infection.

Tucey Timothy M TM Verma Jiyoti J Harrison Paul F PF Snelgrove Sarah L SL Lo Tricia L TL Scherer Allison K AK Barugahare Adele A AA Powell David R DR Wheeler Robert T RT Hickey Michael J MJ Beilharz Traude H TH Naderer Thomas T Traven Ana A

Cell metabolism 20180501 5

To fight infections, macrophages undergo a metabolic shift whereby increased glycolysis fuels antimicrobial inflammation and killing of pathogens. Here we demonstrate that the pathogen Candida albicans turns this metabolic reprogramming into an Achilles' heel for macrophages. During Candida-macrophage interactions intertwined metabolic shifts occur, with concomitant upregulation of glycolysis in both host and pathogen setting up glucose competition. Candida thrives on multiple carbon sources, bu ...[more]

PMID: 29719235

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Project description: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 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.

Dataset Information

Glucose Homeostasis Is Important for Immune Cell Viability during Candida Challenge and Host Survival of Systemic Fungal Infection.

Publications

Glucose Homeostasis Is Important for Immune Cell Viability during Candida Challenge and Host Survival of Systemic Fungal Infection.

Similar Datasets

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