Host insulin hijacking by a nematode receptor mediates developmental plasticity and sex ratio shifts.

Parasitic nematodes encode a limited repertoire of insulin/insulin-like peptides (INS/ILPs) which are expressed primarily in free-living stages, suggesting that host insulin may serve as a critical agonist during parasitism. In this study, we demonstrate that mammalian parasitic nematodes exploit host insulin via their conserved insulin/insulin-like growth factor receptor (IGFR/DAF-2) to drive infection and reproduction in vitro and in vivo. Specifically, host insulin supplementation promotes the biosynthesis of the steroid hormone Δ7-dafachronic acid, the activation of nuclear receptor DAF-12, the infective-to-parasitic transition, and the larval motility and growth in Haemonchus contortus, a model gastrointestinal blood-feeding nematode. Structural analyses suggest that H. contortus IGFR/DAF-2 can bind host (Ovis aries) insulin with predicted affinity comparable to endogenous peptides while engaging a distinct receptor-binding site. Notably, RNAi-mediated silencing of daf-2 impairs larval development, reduces worm burden, and compromises egg production in host animals. Furthermore, we uncover a novel role for insulin signalling in regulating the nematode female-to-male ratio, possibly through sex determination or selective female mortality, specifically affecting female development and reproduction. These findings establish the ligand-receptor co-option of host insulin signalling as an evolutionary adaptation to parasitism and identify IGFR/DAF-2 as a potential target for controlling nematode infection, transmission, and population dynamics.