Kirsten K. Hanson, Ana S Ressurreição, Kathrin Buchholz
Jul 8, 2013
Citations
4
Influential Citations
75
Citations
Quality indicators
Journal
Proceedings of the National Academy of Sciences
Abstract
Significance Plasmodium parasites have two distinct intracellular growth stages inside the mammalian host—the first stage, which is clinically silent, in liver hepatocytes, and the second, which causes the symptoms of malaria, in red blood cells. This study reports the discovery of a class of antimalarial compounds called torins, which are extremely potent inhibitors of both intracellular stages of Plasmodium. We show that torins block trafficking of liver stage parasite proteins to the physical host–parasite interface, called the parasitophorous vacuole membrane (PVM), and that without continuous trafficking of PVM-resident proteins, the parasite is subject to elimination by its host hepatocyte. Residence within a customized vacuole is a highly successful strategy used by diverse intracellular microorganisms. The parasitophorous vacuole membrane (PVM) is the critical interface between Plasmodium parasites and their possibly hostile, yet ultimately sustaining, host cell environment. We show that torins, developed as ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitors, are fast-acting antiplasmodial compounds that unexpectedly target the parasite directly, blocking the dynamic trafficking of the Plasmodium proteins exported protein 1 (EXP1) and upregulated in sporozoites 4 (UIS4) to the liver stage PVM and leading to efficient parasite elimination by the hepatocyte. Torin2 has single-digit, or lower, nanomolar potency in both liver and blood stages of infection in vitro and is likewise effective against both stages in vivo, with a single oral dose sufficient to clear liver stage infection. Parasite elimination and perturbed trafficking of liver stage PVM-resident proteins are both specific aspects of torin-mediated Plasmodium liver stage inhibition, indicating that torins have a distinct mode of action compared with currently used antimalarials.