Diversification of mammalian deltaviruses by host shifting

Significance Satellites are virus-like agents which require both a host and a virus to complete their life cycle. The only human-infecting satellite is hepatitis delta virus (HDV), which exacerbates liver disease in patients co-infected with hepatitis B virus (HBV). How HDV originated is a long-standing evolutionary puzzle. Using terabase-scale data mining, coevolutionary analyses, and field studies in bats, we show that deltaviruses can jump between highly divergent host species. Our results further suggest that the contemporary association between HDV and HBV likely arose following zoonotic transmission from a yet-undiscovered animal reservoir in the Americas. Plastic host and virus associations open prospects that deltaviruses might alter the virulence of multiple viruses in multiple host species. Hepatitis delta virus (HDV) is an unusual RNA agent that replicates using host machinery but exploits hepatitis B virus (HBV) to mobilize its spread within and between hosts. In doing so, HDV enhances the virulence of HBV. How this seemingly improbable hyperparasitic lifestyle emerged is unknown, but it underpins the likelihood that HDV and related deltaviruses may alter other host–virus interactions. Here, we show that deltaviruses diversify by transmitting between mammalian species. Among 96,695 RNA sequence datasets, deltaviruses infected bats, rodents, and an artiodactyl from the Americas but were absent from geographically overrepresented Old World representatives of each mammalian order, suggesting a relatively recent diversification within the Americas. Consistent with diversification by host shifting, both bat and rodent-infecting deltaviruses were paraphyletic, and coevolutionary modeling rejected cospeciation with mammalian hosts. In addition, a 2-y field study showed common vampire bats in Peru were infected by two divergent deltaviruses, indicating multiple introductions to a single host species. One vampire bat-associated deltavirus was detected in the saliva of up to 35% of individuals, formed phylogeographically compartmentalized clades, and infected a sympatric bat, illustrating horizontal transmission within and between species on ecological timescales. Consistent absence of HBV-like viruses in two deltavirus-infected bat species indicated acquisitions of novel viral associations during the divergence of bat and human-infecting deltaviruses. Our analyses support an American zoonotic origin of HDV and reveal prospects for future cross-species emergence of deltaviruses. Given their peculiar life history, deltavirus host shifts will have different constraints and disease outcomes compared to ordinary animal pathogens.