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Rhoptry secretion system structure and priming in Plasmodium falciparum revealed using in situ cryo-electron tomography

Nature Microbiology volume 7, pages 1230–1238 (2022)Cite this article

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Abstract

Apicomplexan parasites secrete contents of the rhoptries, club-shaped organelles in the apical region, into host cells to permit their invasion and establishment of infection. The rhoptry secretory apparatus (RSA), which is critical for rhoptry secretion, was recently discovered in Toxoplasma and Cryptosporidium. It is unknown whether a similar molecular machinery exists in the malaria parasite Plasmodium. In this study, we use in situ cryo-electron tomography to investigate the rhoptry secretion system in P. falciparum merozoites. We identify the presence of an RSA at the cell apex and a morphologically distinct apical vesicle docking the tips of the two rhoptries to the RSA. We also discover two additional rhoptry organizations that lack the apical vesicle. Using subtomogram averaging, we reveal different conformations of the RSA structure corresponding to different rhoptry organizations. Our results highlight previously unknown steps in the process of rhoptry secretion and indicate a regulatory role for the conserved apical vesicle in host invasion by apicomplexan parasites.

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Fig. 1: P. falciparum merozoites harbour an apical vesicle that docks the rhoptries to the parasite plasma membrane.
Fig. 2: Various observed morphological states of the rhoptry secretion system.
Fig. 3: In situ structure of the multicomponent rhoptry secretory apparatus of P. falciparum.
Fig. 4: Comparison of the RSA structures of P. falciparum, T. gondii and C. parvum.
Fig. 5: Different P. falciparum RSA conformations were resolved corresponding to different morphological states of the rhoptry secretion system.
Fig. 6: Working model for the priming of rhoptry secretion in P. falciparum merozoites.

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Data availability

Representative tomograms showing different morphological states of P. falciparum rhoptry fusion (Fig. 2a,b,d) are available in the Electron Microscopy Data Bank (EMDB) under accession codes EMD-26745 (Fig. 2a), EMD-26746 (Fig. 2b) and EMD-26747 (Fig. 2d). Subtomogram averages of the P. falciparum RSA in different conformations are available in the EMDB under accession codes EMD-26670 (RSA-A), EMD-26671 (RSA-2R) and EMD-26672 (RSA-1R). Source data are provided with this paper.

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Acknowledgements

We thank S. Steimle for technical assistance with the Titan Krios G3i cryogenic electron microscope, the Singh Center for Nanotechnology and the Beckman Center for Cryo-Electron Microscopy at the University of Pennsylvania for hosting and supporting the use of the Titan Krios; D. Hodge in the lab of A.R.O.J. for training in P. falciparum culture techniques; L. Theveny from the lab of Y.-W.C. for providing subtomogram averages of the T. gondii and C. parvum RSAs; and other members of the labs of Y.-W.C., A.R.O.J. and M.L. for overall support and useful discussions. This work was supported in part by a David and Lucile Packard Fellowship for Science and Engineering (2019–69645) and a Pennsylvania Department of Health FY19 Health Research Formula Fund to Y.-W.C.; a Martin and Pamela Winter Infectious Disease Fellowship to M.M.; the Mary L. and Matthew S. Santirocco College Alumni Society Undergraduate Research Grant to W.D.C.; an EMBO fellowship (ALTF 58–2018) to A.G.; NIH/NIAID R01 AI103280, R21 AI123808, R21 AI130584 and R61 DH105594 to A.R.O.J. who is an Investigator in the Pathogenesis of Infectious Diseases (PATH) of the Burroughs Wellcome Fund; and a European Research Council advanced grant 833309 (KissAndSpitRhoptry) to M.L.

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Matthew Martinez, William David Chen, Shrawan Kumar Mageswaran & Yi-Wei Chang

  2. LPHI, UMR 5235 CNRS, Université de Montpellier, Montpellier, France

    Marta Mendonça Cova & Maryse Lebrun

  3. Department of Pediatrics, Division of Infectious Diseases, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Petra Molnár & Audrey R. Odom John

  4. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Amandine Guérin

  5. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Audrey R. Odom John

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Contributions

M.M., M.L. and Y.-W.C. conceptualized and designed the experiments. M.M. cultured and isolated parasites provided by A.R.O.J. M.M.C. provided a protocol and consultations for the efficient isolation of merozoites. P.M. provided further training and useful insights for P. falciparum culture and merozoite isolation. M.M. prepared frozen grids and performed cryo-ET, with training from S.K.M., using an automated data-processing pipeline for on-the-fly tomogram reconstruction that was established by W.D.C., who also provided additional computational support during data collection, processing and management. M.M. analysed the tomograms, performed subtomogram averaging and analysed the RSA structure. W.D.C. performed data analysis of rhoptry volumes. S.K.M., A.G., M.M.C. and M.L. provided important insights for the interpretation of data. M.M. prepared the manuscript, with critical inputs and revisions from all authors.

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Correspondence to Yi-Wei Chang.

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Nature Microbiology thanks Friedrich Frischknecht, Ke Hu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 The apical complex and apical vesicle of P. falciparum merozoites.

(a) Simplified schematic of a P. falciparum merozoite apical region. (b–d) 2-D slices through a tomogram of a top-down view of the merozoite apical complex with color overlays of all the observed apical end components: apical vesicle (AV; pink), parasite plasma membrane (PPM; blue), rhoptry (orange), rhoptry secretory apparatus (RSA; light blue), microneme (yellow), inner membrane complex (IMC; green), preconoidal rings (brown), apical polar ring (purple), and subpellicular microtubules (cyan). The cross-sectional planes used in b-d are arranged such that they start at the parasite apex and move inwards into the cell. Scale bar = 100 nm. (e, f) Additional examples of 2-D slices of the AV and rhoptry (left). Blue and orange lines across the AV and rhoptry, respectively, denote the locations of pixel values plotted on the right. Arrows in the pixel plots point to peaks in values corresponding to membranes. Scale bars = 50 nm.

Source data

Extended Data Fig. 2 2-D slices through the P. falciparum merozoite apical complex.

(a–c) 2-D slices from tomograms showing either one rhoptry (a, b) or no rhoptries (c) docked at the AV. Scale bars = 50 nm. (d) 2-D slice from a P. falciparum merozoite apical end tomogram within a mature schizont, adapted from [30]. (e) The same 2-D slice from panel j with the original color overlay of the rhoptry of interest, according to [30]. (f) The same 2-D slice from panel j with an updated color overlay of the rhoptry of interest, the AV, and the RSA, based on our analysis. Scale bars = 200 nm.

Extended Data Fig. 3 Comparison of the apical vesicles from P. falciparum, T. gondii, and C. parvum.

(a) Representative 2-D slices of tomograms displaying the AV from each organism (left – P. falciparum; middle – T. gondii; and right – C. parvum), highlighting the PPM (dark blue), RSA (light blue), AV (pink), and rhoptries (orange). Scale bars = 50 nm. (b) Plots of the shortest distance (AVdist) between the PPM apex and the AV membrane from several cells in each organism, showing the mean ±s.d.. (c) Plots of the major (AVmaj) versus minor axis (AVmin) of the AV from each organism, showing mean ±s.d.. (d) Plots of the angle (Ψ at which the major axis of the AV is oriented with respect to the line connecting the PPM apex and the AV centroid each organism. The median value is shown. N = 39 AVs for P. falciparum, 25 AVs for T. gondii, and 28 AVs for C. parvum.

Source data

Extended Data Fig. 4 Various fusion states of the P. falciparum rhoptries.

(a–c) 2-D slices through tomograms of apical ends showing the absence of the apical vesicle at the rhoptry tips and either bulging of one rhoptry towards the other (a, b) or twisting of the rhoptries (c). Dashed orange lines in panel c denote the portion of the rhoptry neck that is out of view. A mesh of electron-dense material (green) can be observed between rhoptries (orange) that display bulging towards the other. One rhoptry is docked directly at the RSA (purple). (d, e) Examples in which the two rhoptries are fused together and docked directly at the RSA. (f, g) Examples in which only one, very large rhoptry with no discernable neck region was observed and docked directly at the RSA. Scale bars = 100 nm.

Extended Data Fig. 5 Subtomogram averages of the P. falciparum RSA.

(a) Schematic of the RSA, apical vesicle, and PPM demonstrating the top view and side view orientations used to generate 2-D slices of the subtomogram averages. (b, c) Side views (b) and top view (c) of the subtomogram average of the RSA-A structure before applying 8-fold symmetry. Left to right panels: from peripheral to central cross sections (b) or from extracellular to intracellular cross sections (c). (d–g) Side views (d, f) and top view (e, g) of the subtomogram average of the RSA-2R structure, before and after applying 8-fold symmetry. (h–k) Side views (h, j) and top views (i, k) of the subtomogram average of the RSA-1R structure, before and after applying 8-fold symmetry. (l) Gold standard Fourier shell correlation plot of the final, 8-fold symmetrized subtomogram averages of the three RSA structures. Scale bars = 10 nm.

Extended Data Fig. 6 Representative cryo-ET images of the P. falciparum AV and RSA.

(a-j) 2-D slices with of merozoite apexes (left panels) with color overlays (right panels) highlighting the RSA (light blue), the AV (pink), and the connections from the RSA A-II/III densities to the AV (encircled in red dashed lines). Scale bars = 50 nm.

Supplementary information

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Supplementary Video 1

Three-dimensional view of the subtomogram average of the P. falciparum RSA-A structure.

Supplementary Video 2

Subtomogram average of the P. falciparum RSA-A (left), RSA-2R (middle) and RSA-1R (right) structures slicing first through the top view from extracellular to intracellular and back, followed by slicing through the side views.

Supplementary Video 3

Three-dimensional view of the P. falciparum RSA structure, highlighting conformational changes between the RSA-A and RSA-1R states.

Source data

Source Data Fig. 1

Tables of plotted values for Fig. 1d, e and h–l.

Source Data Fig. 2

Tables of plotted values for Fig. 2e and f.

Source Data Fig. 5

Table of plotted values for Fig. 5e.

Source Data Extended Data Fig. 1

Tables of plotted values for Extended Data Fig. 1e and f.

Source Data Extended Data Fig. 3

Tables of plotted values for Extended Data Fig. 3b–d.

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Martinez, M., Chen, W.D., Cova, M.M. et al. Rhoptry secretion system structure and priming in Plasmodium falciparum revealed using in situ cryo-electron tomography. Nat Microbiol 7, 1230–1238 (2022). https://doi.org/10.1038/s41564-022-01171-3

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