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Highly dynamic host actin reorganization around developing Plasmodium inside hepatocytes
Publication . Gomes Santos, Carina S. S.; Itoe, Maurice; Afonso, Cristina; Henriques, Ricardo; Gardner, Rui; Sepulveda, Nuno; Simões, Pedro D.; Raquel, Maria Helena; Almeida, António Paulo; Moita, Luis; Frischknecht, Friedrich; Mota, Maria M.
Plasmodium sporozoites are transmitted by Anopheles mosquitoes and infect hepatocytes, where a single sporozoite replicates into thousands of merozoites inside a parasitophorous vacuole. The nature of the Plasmodium-host cell interface, as well as the interactions occurring between these two organisms, remains largely unknown. Here we show that highly dynamic hepatocyte actin reorganization events occur around developing Plasmodium berghei parasites inside human hepatoma cells. Actin reorganization is most prominent between 10 to 16 hours post infection and depends on the actin severing and capping protein, gelsolin. Live cell imaging studies also suggest that the hepatocyte cytoskeleton may contribute to parasite elimination during Plasmodium development in the liver.
Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins
Publication . Hanson, Kirsten K.; Ressurreição, Ana; Buchholz, K.; Prudêncio, Miguel; Herman-Ornelas, J. D.; Rebelo, Maria; Beatty, W. L.; Wirth, D. F.; Hanscheid, Thomas; Moreira, Rui; Marti, M.; Mota, Maria M.
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.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
PTDC/SAU-GMG/100313/2008