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Kiss and spit: the dual roles of Toxoplasma rhoptries

Nature Reviews Microbiology volume 6, pages 79–88 (2008)Cite this article

Key Points

  • Toxoplasma gondii rhoptries are dedicated secretory organelles that are involved in the mechanics of invasion and commandeering of the infected host cell.

  • Rhoptry proteins collaborate with proteins that are released from another secretory organelle, the microneme, to create a circular moving junction at the ring of contact between the parasite and host plasma membranes.

  • Rhoptry proteins, including protein kinases and phosphatases, are injected into the host cell, where they affect host functions.

  • There is a huge amount of allelic variation in the genes coding for rhoptry proteins and this has a dramatic effect on the outcome of infection.

  • Host range might have been the selective pressure for allelic sequence drift in rhoptry genes.

Abstract

Toxoplasma gondii is a single-celled, eukaryotic parasite that can only reproduce inside a host cell. Upon entry, this Apicomplexan parasite co-opts host functions for its own purposes. An unusual set of apical organelles, named rhoptries, contain some of the machinery that is used by T. gondii both for invasion and to commandeer host functions. Of particular interest are a group of injected protein kinases that are among the most variable of all the T. gondii proteins. At least one of these kinases has a major effect on host-gene expression, including the modulation of key regulators of the immune response. Here, we discuss these recent findings and use them to propose a model in which an expansion of host range is a major force that drives rhoptry-protein evolution.

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Figure 1: Toxoplasma gondii ultrastructure.
Figure 2: Toxoplasma gondii invasion.
Figure 3: Schematic model for rhoptry contribution to invasion.

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References

  1. Luft, B. J. & Remington, J. S. Toxoplasmic encephalitis in AIDS. Clin. Infect. Dis. 15, 211–222 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Dubremetz, J. F., Garcia-Reguet, N., Conseil, V. & Fourmaux, M. N. Apical organelles and host-cell invasion by Apicomplexa. Int. J. Parasitol. 28, 1007–1013 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Dubey, J. P. in Parasitic Protozoa (ed. Kreier, J. P.) 1–158 (Academic, California, 1993).

    Book  Google Scholar 

  4. Pepper, M., Dzierszinski, F., Crawford, A., Hunter, C. A. & Roos, D. Development of a system to study CD4+-T-cell responses to transgenic ovalbumin-expressing Toxoplasma gondii during toxoplasmosis. Infect. Immun. 72, 7240–7246 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gubbels, M. J., Striepen, B., Shastri, N., Turkoz, M. & Robey, E. A. Class I major histocompatibility complex presentation of antigens that escape from the parasitophorous vacuole of Toxoplasma gondii. Infect. Immun. 73, 703–711 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dubey, J. P., Lindsay, D. S. & Speer, C. A. Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts. Clin. Microbiol. Rev. 11, 267–299 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sadak, A., Taghy, Z., Fortier, B. & Dubremetz, J. F. Characterization of a family of rhoptry proteins of Toxoplasma gondii. Mol. Biochem. Parasitol. 29, 203–211 (1988).

    Article  CAS  PubMed  Google Scholar 

  8. Saffer, L. D., Mercereau-Puijalon, O., Dubremetz, J. F. & Schwartzman, J. D. Localization of a Toxoplasma gondii rhoptry protein by immunoelectron microscopy during and after host cell penetration. J. Protozool. 39, 526–530 (1992).

    Article  CAS  PubMed  Google Scholar 

  9. Bradley, P. J. et al. Proteomic analysis of rhoptry organelles reveals many novel constituents for host–parasite interactions in Toxoplasma gondii. J. Biol. Chem. 280, 34245–34258 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Hoppe, H. C., Ngo, H. M., Yang, M. & Joiner, K. A. Targeting to rhoptry organelles of Toxoplasma gondii involves evolutionarily conserved mechanisms. Nature Cell Biol. 2, 449–456 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Bradley, P. J. & Boothroyd, J. C. The pro region of Toxoplasma ROP1 is a rhoptry-targeting signal. Int. J. Parasitol. 31, 1177–1186 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Striepen, B., Soldati, D., Garcia-Reguet, N., Dubremetz, J. F. & Roos, D. S. Targeting of soluble proteins to the rhoptries and micronemes in Toxoplasma gondii. Mol. Biochem. Parasitol. 113, 45–53 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Ngo, H. M. et al. AP-1 in Toxoplasma gondii mediates biogenesis of the rhoptry secretory organelle from a post-Golgi compartment. J. Biol. Chem. 278, 5343–5352 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Bradley, P. J., Li, N. & Boothroyd, J. C. A GFP-based motif-trap reveals a novel mechanism of targeting for the Toxoplasma ROP4 protein. Mol. Biochem. Parasitol. 137, 111–120 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Ngo, H. M., Yang, M. & Joiner, K. A. Are rhoptries in Apicomplexan parasites secretory granules or secretory lysosomal granules? Mol. Microbiol. 52, 1531–1541 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Fevrier, B. & Raposo, G. Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr. Opin. Cell Biol. 16, 415–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. El Hajj, H. et al. The ROP2 family of Toxoplasma gondii rhoptry proteins: proteomic and genomic characterization and molecular modeling. Proteomics 6, 5773–5784 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. El Hajj, H. et al. ROP18 is a rhoptry kinase controlling the intracellular proliferation of Toxoplasma gondii. PLoS Pathog. 3, e14 (2007). The first direct demonstration of the kinase activity of the rhoptry protein ROP18 and its role in T. gondii proliferation in vitro .

    Article  PubMed  PubMed Central  Google Scholar 

  19. Carey, K. L., Jongco, A. M., Kim, K. & Ward, G. E. The Toxoplasma gondii rhoptry protein ROP4 is secreted into the parasitophorous vacuole and becomes phosphorylated in infected cells. Eukaryot. Cell 3, 1320–1330 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gilbert, L. A., Ravindran, S., Turetzky, J. M., Boothroyd, J. C. & Bradley, P. J. Toxoplasma gondii targets a protein phosphatase 2C to the nuclei of infected host cells. Eukaryot. Cell 6, 73–83 (2007). The first study to reveal the targeting of a rhoptry protein to the host-cell nucleus after invasion.

    Article  CAS  PubMed  Google Scholar 

  21. Que, X. et al. The cathepsin B of Toxoplasma gondii, toxopain-1, is critical for parasite invasion and rhoptry protein processing. J. Biol. Chem. 277, 25791–25797 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Miller, S. A., Thathy, V., Ajioka, J. W., Blackman, M. J. & Kim, K. TgSUB2 is a Toxoplasma gondii rhoptry organelle processing proteinase. Mol. Microbiol. 49, 883–894 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Ossorio, P. N., Schwartzman, J. D. & Boothroyd, J. C. A Toxoplasma gondii rhoptry protein associated with host cell penetration has unusual charge asymmetry. Mol. Biochem. Parasitol. 50, 1–15 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Reichmann, G., Dlugonska, H. & Fischer, H. G. Characterization of TgROP9 (p36), a novel rhoptry protein of Toxoplasma gondii tachyzoites identified by T cell clone. Mol. Biochem. Parasitol. 119, 43–54 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Foussard, F., Leriche, M. A. & Dubremetz, J. F. Characterization of the lipid content of Toxoplasma gondii rhoptries. Parasitology 102 Pt 3, 367–370 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. Nichols, B. A., Chiappino, M. L. & O'Connor, G. R. Secretion from the rhoptries of Toxoplasma gondii during host-cell invasion. J. Ultrastruct. Res. 83, 85–98 (1983). First visualization of apparent rhoptry secretion into an infected host cell.

    Article  CAS  PubMed  Google Scholar 

  27. Lebrun, M. et al. The rhoptry neck protein RON4 re-localizes at the moving junction during Toxoplasma gondii invasion. Cell. Microbiol. 7, 1823–1833 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Alexander, D. L., Mital, J., Ward, G. E., Bradley, P. & Boothroyd, J. C. Identification of the moving junction complex of Toxoplasma gondii: a collaboration between distinct secretory organelles. PLoS Pathog. 1, e17 (2005). This paper was the first to identify a cooperation between rhoptry and microneme proteins in invasion. Together with reference 27 it was also the first to show the involvement of RON proteins in the MJ.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Aikawa, M., Miller, L. H., Johnson, J. & Rabbege, J. Erythrocyte entry by malarial parasites: a moving junction between erythrocyte and parasite. J. Cell Biol. 77, 72–82 (1978).

    Article  CAS  PubMed  Google Scholar 

  30. Alexander, D. L., Arastu-Kapur, S., Dubremetz, J. F. & Boothroyd, J. C. Plasmodium falciparum AMA1 binds a rhoptry neck protein homologous to TgRON4, a component of the moving junction in Toxoplasma gondii. Eukaryot. Cell 5, 1169–1173 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kenny, B. et al. Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence into mammalian cells. Cell 91, 511–520 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Hakansson, S., Charron, A. J. & Sibley, L. D. Toxoplasma evacuoles: a two-step process of secretion and fusion forms the parasitophorous vacuole. EMBO J. 20, 3132–3144 (2001). First direct visualization of rhoptry-protein trafficking within an infected cell.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dobrowolski, J. M. & Sibley, L. D. Toxoplasma invasion of mammalian cells is powered by the actin cytoskeleton of the parasite. Cell 84, 933–939 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Beckers, C. J. M., Dubremetz, J. F., Mercereau-Puijalon, O. & Joiner, K. A. The Toxoplasma gondii rhoptry protein ROP2 is inserted into the parasitophorous vauole membrane, surrounding the intracellular parasite, and is exposed to the host cell cytoplasm. J. Cell Biol. 127, 947–961 (1994). First report that rhoptry proteins can be directly exposed to the infected host-cell cytosol.

    Article  CAS  PubMed  Google Scholar 

  35. El Hajj, H., Lebrun, M., Fourmaux, M. N., Vial, H. & Dubremetz, J. F. Inverted topology of the Toxoplasma gondii ROP5 rhoptry protein provides new insights into the association of the ROP2 protein family with the parasitophorous vacuole membrane. Cell. Microbiol. 9, 54–64 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. El Hajj, H., Lebrun, M., Fourmaux, M. N., Vial, H. & Dubremetz, J. F. Characterization, biosynthesis and fate of ROP7, a ROP2 related rhoptry protein of Toxoplasma gondii. Mol. Biochem. Parasitol. 146, 98–100 (2006).

    Article  CAS  Google Scholar 

  37. Herion, P., Hernandez-Pando, R., Dubremetz, J. F. & Saavedra, R. Subcellular localization of the 54-kDa antigen of Toxoplasma gondii. J. Parasitol. 79, 216–222 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Sinai, A., Webster, P. & Joiner, K. Association of host cell endoplasmic reticulum and mitochondria with the Toxoplasma gondii parasitophorous vacuole membrane: a high affinity interaction. J. Cell. Sci. 110, 2117–2128 (1997).

    CAS  PubMed  Google Scholar 

  39. Sinai, A. P. & Joiner, K. A. The Toxoplasma gondii protein ROP2 mediates host organelle association with the parasitophorous vacuole membrane. J. Cell. Biol. 154, 95–108 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Molestina, R. E., Payne, T. M., Coppens, I. & Sinai, A. P. Activation of NF-κB by Toxoplasma gondii correlates with increased expression of antiapoptotic genes and localization of phosphorylated IκB to the parasitophorous vacuole membrane. J. Cell Sci. 116, 4359–4371 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Saeij, J. P. et al. Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature 445, 324–327 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Suss-Toby, E., Zimmerberg, J. & Ward, G. E. Toxoplasma invasion: the parasitophorous vacuole is formed from host cell plasma membrane and pinches off via a fission pore. Proc. Natl Acad. Sci. USA 93, 8413–8418 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gilbert, R. E. et al. Screening for congenital toxoplasmosis: accuracy of immunoglobulin M and immunoglobulin A tests after birth. J. Med. Screen. 14, 8–13 (2007).

    Article  PubMed  Google Scholar 

  44. Ghosh, P. Process of protein transport by the type III secretion system. Microbiol. Mol. Biol. Rev. 68, 771–795 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Saeij, J. P., Boyle, J. P. & Boothroyd, J. C. Differences among the three major strains of Toxoplasma gondii and their specific interactions with the infected host. Trends Parasitol. 21, 476–481 (2005).

    Article  PubMed  Google Scholar 

  46. Saeij, J. P. et al. Polymorphic secreted kinases are key virulence factors in toxoplasmosis. Science 314, 1780–1783 (2006). Demonstrated the major role of two rhoptry proteins (ROP16 and ROP18) in T. gondii virulence in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Taylor, S. et al. A secreted serine-threonine kinase determines virulence in the eukaryotic pathogen Toxoplasma gondii. Science 314, 1776–1780 (2006). Identified the major role that ROP18 has in T. gondii proliferation in vitro and virulence in mice.

    Article  CAS  PubMed  Google Scholar 

  48. Hunter, C. A. & Remington, J. S. The role of IL12 in toxoplasmosis. Res. Immunol. 146, 546–552 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Scharton-Kersten, T., Denkers, E. Y., Gazzinelli, R. & Sher, A. Role of IL12 in induction of cell-mediated immunity to Toxoplasma gondii. Res. Immunol. 146, 539–545 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Jung, C., Lee, C. Y. & Grigg, M. E. The SRS superfamily of Toxoplasma surface proteins. Int. J. Parasitol. 34, 285–296 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Parrish, C. R. & Kawaoka, Y. The origins of new pandemic viruses: the acquisition of new host ranges by canine parvovirus and influenza A viruses. Annu. Rev. Microbiol. 59, 553–586 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Boyle, J. P. et al. Just one cross appears capable of dramatically altering the population biology of a eukaryotic pathogen like Toxoplasma gondii. Proc. Natl Acad. Sci. USA 103, 10514–10519 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lehmann, T., Marcet, P. L., Graham, D. H., Dahl, E. R. & Dubey, J. P. Globalization and the population structure of Toxoplasma gondii. Proc. Natl Acad. Sci. USA 103, 11423–11428 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Holland, G. N. & Lewis, K. G. An update on current practices in the management of ocular toxoplasmosis. Am. J. Ophthalmol. 134, 102–114 (2002).

    Article  PubMed  Google Scholar 

  55. Montoya, J. G. & Liesenfeld, O. Toxoplasmosis. Lancet 363, 1965–1976 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Dubremetz, J. F. Host cell invasion by Toxoplasma gondii. Trends Microbiol. 6, 27–30 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Ferguson, D. J. P. & Dubremetz, J. F. in Toxoplasma gondii: the Model Apicomplexan. Perspectives and Methods (eds. Weiss, L. M. & Kim, K.) 19–48 (Elsevier, London, 2007).

    Book  Google Scholar 

  58. Beckers, C. J., Wakefield, T. & Joiner, K. A. The expression of Toxoplasma proteins in Neospora caninum and the identification of a gene encoding a novel rhoptry protein. Mol. Biochem. Parasitol. 89, 209–223 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Leriche, M. A. & Dubremetz, J. F. Characterization of the protein contents of rhoptries and dense granules of Toxoplasma gondii tachyzoites by subcellular fractionation and monoclonal antibodies. Mol. Biochem. Parasitol. 45, 249–259 (1991).

    Article  CAS  PubMed  Google Scholar 

  60. Park, Y. K. & Nam, H. W. Early recognized antigen (p34) of Toxoplasma gondii after peroral ingestion of tissue cyst forming strain (Me49 strain) in mice. Korean J. Parasitol. 37, 157–162 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Karasov, A. O., Boothroyd, J. C. & Arrizabalaga, G. Identification and disruption of a rhoptry-localized homologue of sodium hydrogen exchangers in Toxoplasma gondii. Int. J. Parasitol. 35, 285–291 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Poupel, O., Boleti, H., Axisa, S., Couture-Tosi, E. & Tardieux, I. Toxofilin, a novel actin-binding protein from Toxoplasma gondii, sequesters actin monomers and caps actin filaments. Mol. Biol. Cell 11, 355–368 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Schwarz, J. A., Fouts, A. E., Cummings, C. A., Ferguson, D. J. & Boothroyd, J. C. A novel rhoptry protein in Toxoplasma gondii bradyzoites and merozoites. Mol. Biochem. Parasitol. 144, 159–166 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Kissinger, J. C., Gajria, B., Li, L., Paulsen, I. T. & Roos, D. S. ToxoDB: accessing the Toxoplasma gondii genome. Nucleic Acids Res. 31, 234–236 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ahn, H. J., Kim, S. & Nam, H. W. Molecular cloning of a rhoptry protein (ROP6) secreted from Toxoplasma gondii. Korean J. Parasitol. 44, 251–254 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank J. Boyle, P. Bradley, M. Lebrun, M. Reese and J. Saeij for critical reading of the manuscript and access to unpublished information. J.C.B. is supported by grants from the National Institutes of Health (RO1 AI21423 and AI75473) and the Ellison Medical Foundation and J.F.D. is supported by grants from the Centre National de la Recherche Scientifique (UMR5539 and ANR 06-MIME-024-01).

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, 94305-5124, California, USA

    John C. Boothroyd

  2. UMR 5539 CNRS, Université de Montpellier 2, CP 107, Place Eugène Bataillon, Montpellier, 34090, France

    Jean-Francois Dubremetz

Authors
  1. John C. Boothroyd
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Corresponding author

Correspondence to John C. Boothroyd.

Supplementary information

Supplementary information S1 (movie)

Toxoplasma gondii invasion. (MOV 2743 kb)

Related links

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DATABASES

Entrez Genome Project

Escherichia coli

Plasmodium falciparum

Toxoplasma gondii

GenBank

RON1

RON2

RON3

RON4

ROP1

ROP2A

ROP4

ROP5

ROP6

ROP7

ROP8

ROP9

ROP10

ROP11

ROP12

ROP13

ROP14

ROP15

ROP16

ROP17

ROP18

TgNHE2

TgPP2C-hn

TgSUB2

Toxofilin

Toxopain1

FURTHER INFORMATION

John C. Boothroyd's homepage

ToxoDB4.2

Glossary

Apicomplexa

A phylum of unicellular eukaryotes that are obligate parasites and defined by a collection of apical organelles that are involved in invasion of a host cell.

Microneme

A small, cylindrical organelle that is found at the periphery of the anterior end of Apicomplexan parasites that secretes its contents onto the surface of a gliding or invading parasite.

Rhoptry

A club-shaped secretory organelle that is found at the anterior end of Apicomplexan parasites that releases its contents during invasion; subdivided into a bulbous base and tapering-neck.

Paralogue

A gene that shares a common evolutionary origin and has evolved in parallel with another gene that is located in the same genome or organism, typically to serve different but related functions.

Orthologue

A gene in one species that shares a common evolutionary origin with a related gene in a different species and that serves essentially the same function.

Parasitophorous vacuole

The vacuole that harbours the parasite.

Moving junction

(MJ). A migrating ring of contact between a host-cell plasma membrane and the surface of an invading parasite.

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Boothroyd, J., Dubremetz, JF. Kiss and spit: the dual roles of Toxoplasma rhoptries. Nat Rev Microbiol 6, 79–88 (2008). https://doi.org/10.1038/nrmicro1800

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