1. Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention.
- Author
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Adderley JD, John von Freyend S, Jackson SA, Bird MJ, Burns AL, Anar B, Metcalf T, Semblat JP, Billker O, Wilson DW, and Doerig C
- Subjects
- Erythrocytes parasitology, Host-Parasite Interactions, Humans, Inhibitory Concentration 50, Life Cycle Stages drug effects, Malaria, Falciparum metabolism, Malaria, Falciparum parasitology, Phosphorylation drug effects, Plasmodium falciparum growth & development, Plasmodium falciparum metabolism, Plasmodium falciparum physiology, Protein Array Analysis, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf metabolism, Proto-Oncogene Proteins c-met antagonists & inhibitors, Proto-Oncogene Proteins c-met metabolism, Antimalarials pharmacology, Erythrocytes metabolism, Plasmodium falciparum drug effects, Protein Kinase Inhibitors pharmacology, Signal Transduction drug effects
- Abstract
Intracellular pathogens mobilize host signaling pathways of their host cell to promote their own survival. Evidence is emerging that signal transduction elements are activated in a-nucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. Here, we fill this knowledge gap through a comprehensive and dynamic assessment of host erythrocyte signaling during infection with Plasmodium falciparum. We used arrays of 878 antibodies directed against human signaling proteins to interrogate the activation status of host erythrocyte phospho-signaling pathways at three blood stages of parasite asexual development. This analysis reveals a dynamic modulation of many host signalling proteins across parasite development. Here we focus on the hepatocyte growth factor receptor (c-MET) and the MAP kinase pathway component B-Raf, providing a proof of concept that human signaling kinases identified as activated by malaria infection represent attractive targets for antimalarial intervention.
- Published
- 2020
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