Maternal Helminths Rewire the Microbiota to Promote Offspring Antiviral Immunity via Indole-3-Propionic Acid

Maternal environmental exposures are critical in shaping offspring immunity. Yet, the role of helminths, mammals’ symbiotic evolutionary partners that have been eliminated from modern societies, remains poorly understood. Here, we show that maternal helminth infection enhances type I interferon (IFN-I) signaling in the offspring’s lung epithelium, conferring broad and lasting protection against respiratory viruses. Using cross-fostering, antibiotics, and gnotobiotic systems, we demonstrate that this antiviral immunity is mediated by helminth-altered maternal microbiota. Mechanistically, we identify the microbial tryptophan metabolite indole-3-propionic acid (IPA) as a key driver of IFN-I responses in lung epithelium. Furthermore, the tryptophan metabolic pathway is enriched in the microbiome of helminth-infected human populations, and IPA alone is sufficient to enhance IFN-I signaling in human bronchial epithelial cells. We uncover a conserved trans-kingdom mechanism by which maternal helminths imprint offspring antiviral immunity and propose that microbial metabolites could be harnessed to restore early-life antiviral defenses in helminth-depleted societies.