Poster Presentation First Malaria World Congress 2018

Interrelationship between Plasmodium development and host cell eryptosis (#413)

Coralie Boulet 1 , Christian Doerig 2 , Teresa G. Carvalho 1
  1. La Trobe University, Bundoora, VIC, Australia
  2. Monash University, Clayton, VIC, Australia

Aims: Like many intracellular pathogens, Plasmodium manipulates host cell signalling pathways to ensure host cell survival during infection. We study the interrelationship between P. falciparum and eryptosis, the programmed cell death of erythrocytes. Numerous features of eryptosis resemble those of classical apoptosis, including exposure of phosphatidylserine on the cell surface. However, the underlying molecular pathways of eryptosis remain poorly understood. Our project aims to (i) define the relationship between Plasmodium and host cell eryptosis, and (ii) identify erythrocyte factors that are essential for parasite survival.

Methods: To study eryptosis, we use a combination of cellular and molecular approaches, including flow cytometry, mass spectrometry, imaging and pharmacological inhibition of key molecules.

Results: Using flow cytometry, we demonstrate that (i) schizont stages, but not ring or trophozoite stages, induce phosphatidylserine exposure of the host cell,  and (ii) P. falciparum induces this phenomenon in bystander uninfected erythrocytes via a secreted signal. Further, treatment of parasite cultures with a chemical inducer of eryptosis that targets the human Raf kinase (BAY-43-9006), affects parasite viability. Interestingly, mature parasite stages are highly susceptible to BAY-induced eryptosis when compared to young stages and uninfected cells.

Conclusions: Eryptosis is observed only in schizont stages, suggestive of a repressive mechanism of eryptosis upon invasion.  Further, a secreted factor induces eryptosis of bystander uninfected erythrocytes, consistent with in vivo observations proposed to be a key factor of severe anaemia during malaria infection. Finally, erythrocyte Raf kinase is key for parasite development. Our work aims to identify druggable targets of the host erythrocyte, which offers perspectives for host-directed therapy. Currently available antimalarial drugs target parasite factors, which allows Plasmodium to develop resistance by selection of beneficial genetic modifications. Identifying and targeting key host cell factors provides a novel perspective for anti-malaria strategies while providing less of an opportunity for drug resistance development.