A recombinant peptide based on PfEMP-1 blocks and reverses adhesion of malaria-infected red blood cells to CD36 under flow.
During falciparum malaria infection, severe complications ensue because parasitized red blood cells (PRBCs) adhere to endothelial cells and accumulate in the microvasculature. At the molecular level, adhesion is mediated by interaction of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1) on the PRBC surface with receptors on the surface of endothelial cells, including CD36. We have shown that a recombinant 179-residue subfragment of PfEMP-1 (rC1-2[1-179]), which encompasses the CD36-binding region, inhibits and reverses adhesion of PRBCs to CD36 under physiologically relevant flow conditions. rC1-2[1-179] inhibited adhesion in a concentration-dependent manner over the range 100 pM to 2 microM, with up to 99% of adhesion blocked at the highest concentration tested. The antiadhesive activity of rC1-2[1-179] was not strain specific and almost totally ablated adhesion of four different parasite lines. Furthermore, rC1-2[1-179] showed remarkable ability to progressively reverse adhesion when flowed over adherent PRBCs for 2h. The effect of rC1-2[1-179] was, however, specific for CD36-mediated adhesion and had no effect on adhesion mediated by CSA. Interference with binding of PRBCs to the vascular endothelium using rC1-2[1-179] or smaller organic mimetics may be a useful therapeutic approach to ameliorate severe complications of falciparum malaria.
Cooke
B M
BM
Department of Microbiology, Monash University, Clayton, Victoria, Australia. brian.cooke@med.monash.edu.au
Nicoll
C L
CL
Baruch
D I
DI
Coppel
R L
RL
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D002448:Cell Adhesion; D002809:Chondroitin Sulfates / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology* / Q000502:physiology*; D018056:Hemorheology; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism; D010963:Plasmodium falciparum / Q000502:physiology*; D015800:Protozoan Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013045:Species Specificity
D018955:CD36 Antigens; D010446:Peptide Fragments; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D002809:Chondroitin Sulfates