Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention

Jack D Adderley,Megan J Bird,Oliver Billker,Danny W Wilson,Sarah A Jackson,Jean-Philippe Semblat,Tom Metcalf,Amy L Burns,Simona John Von Freyend,Christian Doerig,Burcu Anar

doi:10.1038/s41467-020-17829-7

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.

Highlights

Intracellular pathogens mobilize host signaling pathways of their host cell to promote their own survival
To investigate dynamic changes in host erythrocyte signalling during P. falciparum asexual proliferation, we employed an antibody microarray developed by Kinexus (Vancouver, Canada)
The antibody microarray analysis generated a large number of testable hypotheses on the involvement of host erythrocyte signalling proteins during infection by the human malaria parasite P. falciparum

Summary

Introduction

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 anucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. 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. 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. Repurposing anti-cancer kinase inhibitors as agents against infectious diseases would greatly alleviate the lack of resources that severely affects anti-infective drug development

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Results

Conclusion