Open AccessActivation of a PAK‐MEK signalling pathway in malaria parasite‐infected erythrocytes
Author(s) -
Sicard Audrey,
Semblat JeanPhilippe,
Doerig Caroline,
Hamelin Romain,
Moniatte Marc,
DorinSemblat Dominique,
Spicer Julie A.,
Srivastava Anubhav,
Retzlaff Silke,
Heussler Volker,
Waters Andrew P.,
Doerig Christian
Publication year - 2011
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/j.1462-5822.2011.01582.x
Subject(s) - biology , plasmodium berghei , plasmodium falciparum , schizogony , malaria , plasmodium knowlesi , plasmodium (life cycle) , kinome , parasite hosting , parasitemia , microbiology and biotechnology , kinase , immunology , virology , plasmodium vivax , world wide web , computer science
Summary Merozoites of malaria parasites invade red blood cells (RBCs), where they multiply by schizogony, undergoing development through ring, trophozoite and schizont stages that are responsible for malaria pathogenesis. Here, we report that a protein kinase‐mediated signalling pathway involving host RBC PAK1 and MEK1, which do not have orthologues in the Plasmodium kinome, is selectively stimulated in Plasmodium falciparum ‐infected (versus uninfected) RBCs, as determined by the use of phospho‐specific antibodies directed against the activated forms of these enzymes. Pharmacological interference with host MEK and PAK function using highly specific allosteric inhibitors in their known cellular IC 50 ranges results in parasite death. Furthermore, MEK inhibitors have parasiticidal effects in vitro on hepatocyte and erythrocyte stages of the rodent malaria parasite Plasmodium berghei , indicating conservation of this subversive strategy in malaria parasites. These findings have profound implications for the development of novel strategies for antimalarial chemotherapy.