The kinomics of malaria erythrocytic infection

Malaria is one of the most devastating infectious diseases worldwide, causing major public health, social and economic problems globally. The lack of an efficient vaccine and the alarming emergence of resistant parasites to currently available drugs urgently call for the identification of new treatment strategies. Protein kinases are prominent drug targets in cancer and represent highly interesting targets for malaria drug development as well. Our laboratory is a world-leader on the study of functional kinomics of the human malaria parasite Plasmodium falciparum. Unravelling the biological functions of protein kinases of the host cell and of the parasite during infection will inform on specific potential targets for antimalarial drug discovery. In the context of our work on the kinomics of erythrocytes infected with P. falciparum, we made the surprising observation that infection with P. falciparum activates a signalling pathway involving p21-activated kinase (PAK) and MAP/ERK kinase (MEK1) of the host erythrocyte, and that this is required for parasite survival. This prompted us to implement a system-wide approach to assess the modulation of signalling pathways of the host cell by intracellular pathogens. A comprehensive antibody microarray detected dynamic variations in the expression levels and phosphorylation status of host cell signalling proteins during the P. falciparum asexual cycle in erythrocytes. We provided proof of concept that selective small molecule-mediated inhibition of host cell kinases that are among the targets identified by the antibody microarray approach does indeed impair parasite proliferation. This opens the way for host-directed therapy (HTD), a strategy that would limit the emergence of resistance (since the target is not encoded by the parasite).