Rewiring monocyte glucose metabolism via C-type lectin signaling protects against disseminated candidiasis

Abstract

Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyphae was accompanied by metabolic rewiring induced through C-type lectin-signaling pathways. We describe that the innate immune responses against Candida yeast are energy-demanding processes that lead to the mobilization of intracellular metabolite pools and require induction of glucose metabolism, oxidative phosphorylation and glutaminolysis, while responses to hyphae primarily rely on glycolysis. Experimental models of systemic candidiasis models validated a central role for glucose metabolism in anti-Candida immunity, as the impairment of glycolysis led to increased susceptibility in mice. Collectively, these data highlight the importance of understanding the complex network of metabolic responses triggered during infections, and unveil new potential targets for therapeutic approaches against fungal diseases.

A novel strategy for single-cell metabolic analysis highlights dynamic changes in immune subpopulations

“…Deeper subset analysis demonstrated that the inflammatory CD86 + CD16 + monocytes expressed higher HK1, suggesting a greater glycolytic capacity. This supports and clarifies earlier work showing that the activation induced upregulation in the global monocyte population is dependent on glycolysis 50 . In addition our findings show divergent metabolic requirements in the DC subpopulations following activation 51 .…”

Frontline Science: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst

“…Several studies have examined the effects of glucose metabolism upon LPS or bacterial stimulation and showed diverse cellular reprogramming depending on the stimulus, experimental setup, and cell population . Glycolysis is essential for host defense against C. albicans infection . Glycolysis inhibition decreased cytokine response to C. albicans stimulation, but increased upon E. coli or S. aureus stimulation in our experiments.…”

New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

“…In a recent study, Tucey et al showed that C. albicans enhances its glycolytic activity through the transcriptional activators Tye7p and Gal4p after escaping from macrophages, until local glucose is depleted (Tucey et al, 2018). As previously stated, C. albicans activation of macrophages leads to them becoming overly dependent on glucose for use in aerobic glycolysis (Domínguez-Andrés et al, 2017;Tucey et al, 2018). The glucose depletion, together with this overreliance of macrophages on glucose after their own metabolic reprogramming, increases immune cell death (Tucey et al, 2018).…”

“…Interestingly, activation using C. albicans yeasts led to an increase in cellular respiration (an indicator of OxPhos activity), contrasting with the profile exhibited by LPS/IFNγactivated macrophages (El Kasmi and Stenmark, 2015). Blocking glycolysis at different intervention points induces defective pro-inflammatory cytokine release and ROS production, and worse outcomes during in vivo systemic infections (Domínguez-Andrés et al, 2017). Similarly, C. albicans induce NK cells to change their metabolism toward glycolysis, which is required for proper immune and cytolytic responses of this cell type (Hellwig et al, 2016).…”

“…albicans has been shown to induce this metabolic reprogramming in monocytes/macrophages (Traven and Naderer, 2019), although depends on fungal morphology. While both heat-killed yeast and hyphae induce the expression of genes involved in glycolysis and glutaminolysis, hyphae-stimulated cells respond to a lesser extent (Domínguez-Andrés et al, 2017). Interestingly, activation using C. albicans yeasts led to an increase in cellular respiration (an indicator of OxPhos activity), contrasting with the profile exhibited by LPS/IFNγactivated macrophages (El Kasmi and Stenmark, 2015).…”