Format

Send to

Choose Destination
PLoS Pathog. 2015 Feb 27;11(2):e1004670. doi: 10.1371/journal.ppat.1004670. eCollection 2015 Feb.

Revealing the sequence and resulting cellular morphology of receptor-ligand interactions during Plasmodium falciparum invasion of erythrocytes.

Author information

1
Burnet Institute, Melbourne, Australia.
2
Burnet Institute, Melbourne, Australia; Department of Immunology, Monash University, Melbourne, Australia.
3
Burnet Institute, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Australia.
4
Department of Medical Biology, University of Melbourne, Australia; The Walter & Eliza Hall Institute of Medical Research, Parkville, Australia.
5
Burnet Institute, Melbourne, Australia; Department of Microbiology & Immunology, University of Melbourne, Australia.
6
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.
7
Schools of Chemistry and Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
8
Malaria Programme, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
9
Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
10
Burnet Institute, Melbourne, Australia; Department of Immunology, Monash University, Melbourne, Australia; Department of Microbiology & Immunology, University of Melbourne, Australia.

Abstract

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.

PMID:
25723550
PMCID:
PMC4344246
DOI:
10.1371/journal.ppat.1004670
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center