Revealing the sequence and resulting cellular morphology of receptor-ligand interactions during Plasmodium falciparum invasion of erythrocytes.
During blood stage Plasmodium falciparum infection, merozoites invade uninfected erythrocytes via a complex, multistep process involving a series of distinct receptor-ligand binding events. Understanding each element in this process increases the potential to block the parasite's life cycle via drugs or vaccines. To investigate specific receptor-ligand interactions, they were systematically blocked using a combination of genetic deletion, enzymatic receptor cleavage and inhibition of binding via antibodies, peptides and small molecules, and the resulting temporal changes in invasion and morphological effects on erythrocytes were filmed using live cell imaging. Analysis of the videos have shown receptor-ligand interactions occur in the following sequence with the following cellular morphologies; 1) an early heparin-blockable interaction which weakly deforms the erythrocyte, 2) EBA and PfRh ligands which strongly deform the erythrocyte, a process dependant on the merozoite's actin-myosin motor, 3) a PfRh5-basigin binding step which results in a pore or opening between parasite and host through which it appears small molecules and possibly invasion components can flow and 4) an AMA1-RON2 interaction that mediates tight junction formation, which acts as an anchor point for internalization. In addition to enhancing general knowledge of apicomplexan biology, this work provides a rational basis to combine sequentially acting merozoite vaccine candidates in a single multi-receptor-blocking vaccine.
Burnet Institute, Melbourne, Australia.
Greta E
GE
Weiss
Burnet Institute, Melbourne, Australia; Department of Immunology, Monash University, Melbourne, Australia.
Paul R
PR
Gilson
Burnet Institute, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Australia.
Tana
T
Taechalertpaisarn
Department of Medical Biology, University of Melbourne, Australia; The Walter & Eliza Hall Institute of Medical Research, Parkville, Australia.
Wai-Hong
WH
Tham
Burnet Institute, Melbourne, Australia.
Nienke W M
NW
de Jong
Burnet Institute, Melbourne, Australia; Department of Microbiology & Immunology, University of Melbourne, Australia.
Katherine L
KL
Harvey
Burnet Institute, Melbourne, Australia; Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Australia; Department of Epidemiology and Preventive Medicine and Department of Infectious Diseases, Monash University, Melbourne, Australia.
Freya J I
FJ
Fowkes
Schools of Chemistry and Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Paul N
PN
Barlow
Malaria Programme, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Julian C
JC
Rayner
Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Gavin J
GJ
Wright
Department of Medical Biology, University of Melbourne, Australia; The Walter & Eliza Hall Institute of Medical Research, Parkville, Australia.
Alan F
AF
Cowman
Burnet Institute, Melbourne, Australia; Department of Immunology, Monash University, Melbourne, Australia; Department of Microbiology & Immunology, University of Melbourne, Australia.
Brendan S
BS
Crabb
D000818:Animals; D000953:Antigens, Protozoan / Q000378:metabolism; D051926:Basigin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D048430:Cell Shape; D002478:Cells, Cultured; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology; D006790:Host-Parasite Interactions / Q000502:physiology; D008024:Ligands; D016778:Malaria, Falciparum / Q000097:blood* / Q000378:metabolism / Q000469:parasitology*; D008565:Membrane Proteins / Q000378:metabolism; D052940:Merozoites / Q000378:metabolism / Q000473:pathology; D010963:Plasmodium falciparum / Q000378:metabolism / Q000472:pathogenicity*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000378:metabolism; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction
D000953:Antigens, Protozoan; D002352:Carrier Proteins; D008024:Ligands; D008565:Membrane Proteins; D015800:Protozoan Proteins; C531020:RH5 protein, Plasmodium falciparum; D011956:Receptors, Cell Surface; C090077:apical membrane antigen I, Plasmodium; D051926:Basigin; D002118:Calcium