Dual interference with host neuropeptide signaling allows parasitoid wasp to hijack host sugar metabolism.

Changes in host carbohydrate metabolism determine the outcome of host-parasite relationships, but the underlying mechanistic basis remains elusive. Here, we show that the parasitoid wasp Cotesia vestalis induces trehalose accumulation in its host, the moth Plutella xylostella, largely independently of insulin/adipokinetic hormone signalling and food intake. Instead, parasitoids rewire host carbohydrate metabolism via two pathways activated by the evolutionarily conserved short neuropeptide F (sNPF), a functional analogue of mammalian neuropeptide Y. Parasitoid-derived teratocytes secrete sNPF that interacts with the sNPF receptor (sNPFR) on host cells, and contributes to host hypertrehalosemia by promoting glycogenolysis in the fat body. We further find that a parasitoid-symbiotic virus induces expression of host-encoded sNPF, which stimulates glycolysis in the host midgut. Furthermore, we show that the host sNPF-sNPFR complex stimulates G(q)/Ca(2+) signalling, while the parasitoid sNPF, exhibiting higher receptor affinity, triggers G(i)/cAMP signalling. Molecular docking analyses suggest that the observed distinct receptor activation properties may be attributed to structural variations in the sNPF-sNPFR binding pocket. Collectively, our findings uncover an unexpected role of peripheral sNPFs in the regulation of carbohydrate metabolism during host-parasite interactions.