Irreversible effect of cysteine protease inhibitors on the release of malaria parasites from infected erythrocytes.
By studying the inactivation of malaria parasite culture by cysteine protease inhibition using confocal microscopy of living cells and electron microscopy of high-pressure frozen and freeze-substituted cells, we report the precise step in the release of malaria parasites from erythrocytes that is likely regulated by cysteine proteases: the opening of the erythrocyte membrane, liberating parasites for the next round of infection. Inhibition of cysteine proteases within the last few minutes of cycle does not affect rupture of the parasitophorus vacuole but irreversibly blocks the subsequent rupture of the host cell membrane, locking in resident parasites, which die within a few hours of captivity. This irreversible inactivation of mature parasites inside host cells makes plasmodial cysteine proteases attractive targets for antimalarials, as parasite-specific cysteine protease inhibitors may significantly augment multi-target drug cocktails.
Glushakova
Svetlana
S
Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Mazar
Julia
J
Hohmann-Marriott
Martin F
MF
Hama
Erinn
E
Zimmerberg
Joshua
J
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002462:Cell Membrane / Q000648:ultrastructure; D020285:Cryoelectron Microscopy; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D007425:Intracellular Membranes / Q000648:ultrastructure; D018613:Microscopy, Confocal; D010963:Plasmodium falciparum / Q000187:drug effects*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D014617:Vacuoles / Q000469:parasitology / Q000648:ultrastructure
D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases