Recognition of yeast β-glucan particles triggers immunometabolic signalling required for trained immunity

Fungal β-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in β-glucan source, structure and solubility alters interaction with the phagocytic receptor Dectin-1 and could impact strategies to improve trained immunity in humans. Using a panel of diverse β-glucans we describe the ability of a specific yeast-derived whole-glucan particle (WGP) to reprogramme metabolism and thereby drive trained immunity in human monocyte-derived macrophages in vitro and mice bone-marrow in vivo. Presentation of pure, non-soluble, non-aggregated WGPs led to the formation of the Dectin-1 phagocytic synapse with subsequent lysosomal mTOR activation, metabolic reprogramming and epigenetic rewiring. Intraperitoneal or oral administration of WGP drove bone-marrow myelopoiesis and improved mature macrophage responses, pointing to therapeutic and food-based strategies to drive trained immunity. Thus, the investment of a cell in a trained response relies on specific recognition of β-glucans presented on intact microbial particles through stimulation of the Dectin-1 phagocytic response.