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.

Virulence and pathogenicity of aCandida albicansmutant with reduced filamentation

“…Macrophage neutralisation by phagocytosed C. albicans is considered to be a two-step process: pyroptosis, an early interaction event, and the cell damage of phagosomes caused by sheer mechanical force of the growing hyphae. The latter event is also dependent on glucose consumption by the intracellular C. albicans (Tucey et al, 2018).…”

“…Macrophage neutralisation by phagocytosed C. albicans is considered to be a two‐step process: pyroptosis, an early interaction event, and the cell damage of phagosomes caused by sheer mechanical force of the growing hyphae. The latter event is also dependent on glucose consumption by the intracellular C. albicans (Tucey et al, ). Pyroptosis involves NLRP3 inflammasome and activation of caspase‐1 that leads to the release of pro‐inflammatory cytokines through pores in the cell membrane and the subsequent cell swelling leading to host cell lysis (Uwamahoro et al, ; Wellington et al, ).…”

Central metabolic interactions of immune cells and microbes: prospects for defeating infections

“…We note that many of the studies that we discussed used LPS stimulation as a proxy for bacterial infection, with validation with whole bacteria rarely performed. Nevertheless, challenge of primary mouse macrophages and human peripheral blood mononuclear cells (PBMCs) with the yeast pathogen Candida albicans resulted in similar metabolic changes to those seen with LPS [43,44]. However, differences compared to LPS have been reported in other cases.…”

“…While immunometabolic shifts are meant to help the host to defeat the infection, in some instances microbes might benefit from the changes in metabolite levels that result from host metabolic reprogramming [74][75][76][77]. Furthermore, it is also possible for the microbial pathogen to seize the opportunity and turn the immunometabolic reprogramming of host cells into a nutritional disadvantage [44]. Below we review the metabolic strategies of key microbial pathogens and discuss the concept of microbes turning the tables on immune cells during their metabolic interactions.…”

“…The situation with fatty acid oxidation is less clear [91,92]. At least in part, utilisation of non-glucose carbon sources by C. albicans stems from the necessity to survive and grow within macrophages, because phagocytosed C. albicans upregulates enzymes of the glyoxylate shunt, gluconeogenesis and fatty acid oxidation [44,93]. Transcription of enzymes needed to utilise nonglucose carbon source was also detected in C. albicans facing human blood [94,95], in a model of epithelial infection [96], in vivo in mouse infections [97][98][99] and in isolates obtained from AIDS patients suffering from mucosal candidiasis [96].…”