Targeting immunometabolism in host-directed therapies to fungal disease

Abstract

Fungal infections affect over a billion people and are responsible for more than 1.5 million deaths each year. Despite progress in diagnostic and therapeutic approaches, the management of severe fungal infections remains a challenge. Recently, the reprogramming of cellular metabolism has emerged as a central mechanism through which the effector functions of immune cells are supported to promote antifungal activity. An improved understanding of the immunometabolic signatures that orchestrate antifungal immunity, together with the dissection of the mechanisms that underlie heterogeneity in individual immune responses, may therefore unveil new targets amenable to adjunctive host-directed therapies. In this review, we highlight recent advances in the metabolic regulation of host-fungus interactions and antifungal immune responses, and outline targetable pathways and mechanisms with promising therapeutic potential.

Keywords: antifungal immunity; fungal disease; host-directed therapy; immunometabolism; immunotherapy.

Graphical Abstract

Fig. 1

Metabolic reprogramming of myeloid cells in response to fungal infection. Recognition of fungal pathogens by pathogen recognition receptors (PRRs) is accompanied by the upregulation of glycolysis and production of lactate. In these conditions, the TCA cycle and oxidative phosphorylation (OxPhos) are often repressed, resulting in the accumulation of intermediates such as succinate and itaconate, and enhancing the generation of reactive oxygen and nitrogen species. In response to C. albicans, the activation of glycolysis is triggered by the recognition of β-glucan by dectin-1, a process that can be in turn exploited by the fungus through its ability to compete for glucose and ultimately promote macrophage death. Sensing of lactate secreted by immune cells also drives the masking of β-glucans in the fungal cell wall and immune evasion. The activation of glycolysis during infection with A. fumigatus is instead triggered by the release of melanin during germination. By sequestering calcium within the phagosome, melanin promotes the recruitment of mTOR which, in turn, mediates the activation of downstream metabolic genes and regulators. The catabolism of tryptophan (Trp) by the indoleamine-2,3-dioxygenase 1 (IDO1) enzyme also regulates antifungal immune responses and controls fungal morphology through its downstream catabolites, collectively referred to as kynurenines (Kyn).

Fig. 2

Trained immunity as a tool to potentiate host defense. Microbial or endogenous stimuli activate innate immune cells. Depending on the dose or stimuli, innate immune function may be increased when encountering a secondary stimulation (trained immunity) or cells may become unresponsive or anti-inflammatory (tolerance). Trained immunity confers long-term protection thought the myelopoietic skewing of hematopoietic stem cells, giving rise to monocytes with enhanced effector functions. They rely on metabolic changes, such as increased glycolysis and OxPhos, which supports epigenetic rewiring that promotes the expression of proinflammatory genes culminating in the increased secretion of cytokines. Thus, trained immunity inducers may be an attractive therapeutic tool to revert tolerance, possibly rescuing states of immune paralysis in sepsis and decreasing the risk of secondary infections.