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Excreted Trypanosoma brucei proteins inhibit Plasmodium hepatic infection
Publication . Temporão, Adriana; Sanches-Vaz, Margarida; Luís, Rafael; Nunes-Cabaço, Helena; Smith, Terry K.; Prudêncio, Miguel; Figueiredo, Luisa M.
Malaria, a disease caused by Plasmodium parasites, remains a major threat to public health globally. It is the most common disease in patients with sleeping sickness, another parasitic illness, caused by Trypanosoma brucei. We have previously shown that a T. brucei infection impairs a secondary P. berghei liver infection and decreases malaria severity in mice. However, whether this effect requires an active trypanosome infection remained unknown. Here, we show that Plasmodium liver infection can also be inhibited by the serum of a mouse previously infected by T. brucei and by total protein lysates of this kinetoplastid. Biochemical characterisation showed that the anti-Plasmodium activity of the total T. brucei lysates depends on its protein fraction, but is independent of the abundant variant surface glycoprotein. Finally, we found that the protein(s) responsible for the inhibition of Plasmodium infection is/are present within a fraction of ~350 proteins that are excreted to the bloodstream of the host. We conclude that the defence mechanism developed by trypanosomes against Plasmodium relies on protein excretion. This study opens the door to the identification of novel antiplasmodial intervention strategies.
Pre-erythrocytic activity of M5717 in monotherapy and combination in preclinical Plasmodium infection models
Publication . Fontinha, Diana; Arez, Francisca; Gal, Isabella Ramella; Nogueira, Gonçalo; Moita, Diana; Baeurle, Tobias Hyun Ho; Brito, Catarina; Spangenberg, Thomas; Alves, Paula M.; Prudêncio, Miguel
Combination therapies have emerged to mitigate Plasmodium drug resistance, which has hampered the fight against malaria. M5717 is a potent multistage antiplasmodial drug under clinical development, which inhibits parasite protein synthesis. The combination of M5717 with pyronaridine, an inhibitor of hemozoin formation, displays potent activity against blood stage Plasmodium infection. However, the impact of this therapy on liver infection by Plasmodium remains unknown. Here, we employed a recently described 3D culture-based hepatic infection platform to evaluate the activity of the M5717-pyronaridine combination against hepatic infection by P. berghei. This effect was further confirmed in vivo by employing the C57BL/6J rodent Plasmodium infection model. Collectively, our data demonstrate that pyronaridine potentiates the activity of M5717 against P. berghei hepatic development. These preclinical results contribute to the validation of pyronaridine as a suitable partner drug for M5717, supporting the clinical evaluation of this novel antiplasmodial combination therapy.
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Fundação para a Ciência e a Tecnologia
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CEEC IND 2017
Número da atribuição
CEECIND/03539/2017/CP1396/CT0009