Helminth infection confers transient antibacterial immunity via IL-4–trained tissue macrophages

Abstract Helminth infection is generally thought to undermine antimicrobial defence; however, we find that a single Heligmosomoides polygyrus bakeri infection leaves mice systemically protected against lethal Staphylococcus aureus challenge for weeks after anthelmintic treatment. This protection does not involve bone-marrow imprinting but depends on expansion and epigenetic reprogramming of resident peritoneal macrophages, sustained by a persistent Th2 population. Transcriptomic and chromatin analyses identify IL-4/IL-4Rα—driven Cybb upregulation and heightened reactive oxygen species production as key effectors, while eosinophils and basophils are dispensable. Our results reveal an adaptive-to-innate, type-2-dominated training pathway that imparts short-term systemic antibacterial immunity, reframing helminth infections as potential modulators of host defence and highlighting type-2 pathways as targets for broad-spectrum anti-infective strategies.