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Edited by John C. Boothroyd, Stanford University Medical Center, Stanford, CA, and approved February 15, 2017 (received for review December 1, 2016)
Significance
Malaria parasites develop within red blood cells inside a membrane-enclosed parasitophorous vacuole. An essential step in their life cycle is the exit of mature parasites from the blood cell, a multistage process termed egress. To do this, the parasites orchestrate a highly regulated sequence of membrane permeabilization and breakage steps culminating in the explosive release of parasites for a new round of infection. Here, we describe a previously unidentified permeabilization of the vacuolar membrane at the start of egress, preceding membrane rupture, suggesting a new initiation step in egress. We also show that, in the final minutes of egress, the blood cell membrane abruptly loses its structural rigidity and collapses around the parasites, showing a precise timing for cytoskeletal breakdown.
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.
Footnotes
↵1Present address: Pinelands High School, Pinelands, 7405, South Africa.
- ↵2To whom correspondence should be addressed. Email: h.saibil{at}mail.cryst.bbk.ac.uk.
Author contributions: R.A.F., M.J.B., and H.R.S. designed research; V.L.H., J.M.W., F.H., G.V.-B., C.v.O., J.A.T., M.C.S., and M.H. performed research; E.D. contributed new reagents/analytic tools; V.L.H. analyzed data; and V.L.H., M.J.B., and H.R.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the EM Database for EM tomograms (accession nos. EMD-3586, EMD-3587, EMD-3606, and EMD-3610) and EMPIAR for X-ray tomograms (accession no. EMPIAR-10087).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1619441114/-/DCSupplemental.
Freely available online through the PNAS open access option.
Sequence of steps in malaria parasite egress
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