Low levels of mammalian TGF-β1 are protective against malaria parasite infection, a paradox clarified in the mosquito host

Nitric oxide (NO), derived from catalysis of inducible NO synthase (iNOS), limits malaria parasite growth in mammals. Transforming growth factor (TGF)-β1 suppresses iNOS in cells in vitro as well as in vivo in mice, but paradoxically severe malaria in humans is associated with low levels of TGF-β1. We hypothesized that this paradox is a universal feature of infection and occurs in the mosquito Anopheles stephensi, an invertebrate host for Plasmodium that also regulates parasite development with inducible NO synthase (AsNOS). We show that exogenous human TGF-β1 dose-dependently regulates mosquito AsNOS expression and that parasite killing by low dose TGF-β1 depends on AsNOS catalysis. Furthermore, induction of AsNOS expression by TGF-β1 is regulated by NO synthesis. These results suggest that TGF-β1 plays similar roles during parasite infection in mammals and mosquitoes and that this role is linked to the effects of TGF-β1 on inducible NO synthesis.