TORC1 is an essential regulator of nutrient-dependent differentiation inLeishmania

SUMMARYLeishmaniaparasites undergo differentiation between various proliferating and non-dividing forms to adapt to changing host environments. The mechanisms that link environmental cues with the parasite’s developmental changes remain elusive. Here, we report thatLeishmaniaTORC1 is a key environmental sensor for parasite differentiation in the sand fly-stage promastigotes and for replication of mammalian-stage amastigotes. We show thatLeishmaniaRPTOR1, interacts with TOR1 and LST8. We investigate TORC1 function by conditional deletion ofRPTOR1, where under nutrient rich conditions RPTOR1 depletion results in decreased protein synthesis and growth, G1 cell cycle arrest and premature differentiation from proliferative promastigotes to non-dividing mammalian-infective metacyclic forms. These parasites cannot develop into proliferative amastigotes in the mammalian host, or respond to nutrients to differentiate to proliferative retroleptomonads, which are required for their blood-meal induced amplification in sand flies and enhanced mammalian infectivity. RPTOR1-dependent TORC1 functionality represents a critical mechanism for driving parasite growth and proliferation.