The machinery underlying malaria parasite virulence is conserved between rodent and human malaria parasites.

Mariana De Niz,Tobias Spielmann,Sven Flemming,Alexandra Blancke Soares,Ruth Lyck,Christian Pick,Gesine Kaiser,Ann-Katrin Ullrich,Volker Heussler,Arlett Heiber,Monica Prado,Chris J Janse,Derya Keller,Hernando Del Portillo

doi:10.1038/ncomms11659

Abstract

Sequestration of red blood cells infected with the human malaria parasite Plasmodium falciparum in organs such as the brain is considered important for pathogenicity. A similar phenomenon has been observed in mouse models of malaria, using the rodent parasite Plasmodium berghei, but it is unclear whether the P. falciparum proteins known to be involved in this process are conserved in the rodent parasite. Here we identify the P. berghei orthologues of two such key factors of P. falciparum, SBP1 and MAHRP1. Red blood cells infected with P. berghei parasites lacking SBP1 or MAHRP1a fail to bind the endothelial receptor CD36 and show reduced sequestration and virulence in mice. Complementation of the mutant P. berghei parasites with the respective P. falciparum SBP1 and MAHRP1 orthologues restores sequestration and virulence. These findings reveal evolutionary conservation of the machinery underlying sequestration of divergent malaria parasites and support the notion that the P. berghei rodent model is an adequate tool for research on malaria virulence.

Highlights

Sequestration of red blood cells infected with the human malaria parasite Plasmodium falciparum in organs such as the brain is considered important for pathogenicity
Sequestration of P. falciparum parasites is mediated by the major virulence factor PfEMP1, a protein transported to the infected red blood cells (iRBCs) surface that enables binding to endothelial host cell receptors such as CD36 and ICAM1
The only protein so far shown to be essential for P. berghei CD36-mediated sequestration of schizont-infected RBC is a PEXEL-positive exported protein, the schizont membrane-associated cytoadherence protein (SMAC), a molecule restricted to rodent malaria parasites that is found in the cytoplasm of iRBCs but not on their surface[8]

Summary

Introduction

Sequestration of red blood cells infected with the human malaria parasite Plasmodium falciparum in organs such as the brain is considered important for pathogenicity. Sequestration of P. falciparum parasites is mediated by the major virulence factor PfEMP1, a protein transported to the iRBC surface that enables binding to endothelial host cell receptors such as CD36 and ICAM1 In the host cell an elaborate machinery mediates further transport of PfEMP1 to the iRBC surface and the proper surface display required for cytoadherence[17,18,19,20] This machinery was so far considered to be specific for the transport of PfEMP1 in P. falciparum and does not seem to be required for the trafficking of other exported proteins[17,18,19,20]. The only protein so far shown to be essential for P. berghei CD36-mediated sequestration of schizont-infected RBC is a PEXEL-positive exported protein, the schizont membrane-associated cytoadherence protein (SMAC), a molecule restricted to rodent malaria parasites that is found in the cytoplasm of iRBCs but not on their surface[8]. Our data indicate evolutionary conservation of the machinery underlying parasite virulence and highlight the P. berghei rodent model as an adequate tool to analyse factors involved in malaria virulence

Methods

Results

Conclusion