Poster Presentation First Malaria World Congress 2018

Host erythrocyte phospho-signalling during infection with Plasmodium falciparum (#221)

Jack Adderley 1 , Simona John von Freyend , Christian Doerig
  1. Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria, Australia

The recent emergence of artemisinin resistance in South East Asia underlines the urgent need for antimalarial drugs with novel mechanisms of action. With this purpose in mind, our laboratory is exploring the role human kinases are playing in the survival of Plasmodium falciparum in erythrocytes. To comprehensively assess the involvement of host erythrocyte signalling during infection, we implemented an approach based on a microarray of >900 antibodies directed against human signalling proteins.  >50% of these antibodies are phospho-specific and hence allow the determination of the activation status of kinases and other proteins. Time-course analysis of the mobilisation of host cell pathways during infection revealed that a large number of host erythrocyte signalling proteins are modulated in a dynamic way by infection, including the receptor tyrosine kinases (RTKs) c-MET and ALK. The P. falciparum kinome does not include any kinases from this group. However, we showed that compounds that are highly selective against c-MET (Crizotinib, PHA-665752) and ALK (Certinib) have sub-micromolar IC50s on parasite proliferation. The array data also show that several downstream components of the c-MET/ALK pathways are also activated following infection. Taken together, these observations strongly suggest that host erythrocyte RTKs and their downstream pathways play a crucial role in parasite proliferation and/or survival, and open the way to host-directed strategies in antimalarial drug discovery and development.