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Parasitophorous vacuole poration precedes its rupture and rapid host erythrocyte cytoskeleton collapse in Plasmodium falciparum egress

DOI: 10.1073/pnas.1619441114 DOI Help

Authors: Victoria Hale (Birkbeck College, London) , Jean M. Watermeyer (Birkbeck College, London) , Fiona Hackett (Francis Crick Institute) , Gema Vizcay-barrena (Kings College London) , Christiaan Van Ooij (Francis Crick Institute) , James A. Thomas (Francis Crick Institute) , Matthew C. Spink (Diamond Light Source) , Maria Harkiolaki (Diamond Light Source) , Elizabeth Duke (Diamond Light Source) , Roland A. Fleck (King's College London) , Michael J. Blackman (Francis Crick Institute, London; London School of Hygiene and Tropical Medicine) , Helen Saibil (Birkbeck College, London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences

State: Published (Approved)
Published: March 2017
Diamond Proposal Number(s): 14410

Abstract: In the asexual blood stages of malarial infection, merozoites invade erythrocytes and replicate within a parasitophorous vacuole to form daughter cells that eventually exit (egress) by sequential rupture of the vacuole and erythrocyte membranes. The current model is that PKG, a malarial cGMP-dependent protein kinase, triggers egress, activating malarial proteases and other effectors. Using selective inhibitors of either PKG or cysteine proteases to separately inhibit the sequential steps in membrane perforation, combined with video microscopy, electron tomography, electron energy loss spectroscopy, and soft X-ray tomography of mature intracellular Plasmodium falciparum parasites, we resolve intermediate steps in egress. We show that the parasitophorous vacuole membrane (PVM) is permeabilized 10–30 min before its PKG-triggered breakdown into multilayered vesicles. Just before PVM breakdown, the host red cell undergoes an abrupt, dramatic shape change due to the sudden breakdown of the erythrocyte cytoskeleton, before permeabilization and eventual rupture of the erythrocyte membrane to release the parasites. In contrast to the previous view of PKG-triggered initiation of egress and a gradual dismantling of the host erythrocyte cytoskeleton over the course of schizont development, our findings identify an initial step in egress and show that host cell cytoskeleton breakdown is restricted to a narrow time window within the final stages of egress.

Journal Keywords: malaria; egress; electron tomography; soft X-ray microscopy; electron energy loss spectroscopy

Subject Areas: Biology and Bio-materials


Instruments: B24-Cryo Soft X-ray Tomography

Added On: 16/03/2017 14:50

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