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Toxoplasma protein export and effector function

Nature Microbiology volume 9, pages 17–28 (2024)Cite this article

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Abstract

Toxoplasma gondii is a single-celled eukaryotic parasite with a considerable host range that must invade the cells of warm-blooded hosts to survive and replicate. The challenges and opportunities that such a strategy represent have been met by the evolution of effectors that are delivered into host cells, counter host defences and co-opt host cell functions for their own purposes. These effectors are delivered in two waves using distinct machinery for each. In this Review, we focus on understanding the architecture of these protein-export systems and how their protein cargo is recognized and selected. We discuss the recent findings on the role that host manipulation has in latent Toxoplasma infections. We also discuss how these recent findings compare to protein export in the related Plasmodium spp. (the causative agent of malaria) and how this can inform our understanding of host manipulation in the larger Apicomplexa phylum and its evolution.

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Fig. 1: The first wave of effectors: injection and manipulation by Toxoplasma rhoptry proteins.
Fig. 2: The second wave of effectors: the Toxoplasma dense granule proteins.
Fig. 3: Licencing and translocation of effectors in Toxoplasma and Plasmodium.

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References

  1. Arandjelovic, P., Doerflinger, M. & Pellegrini, M. Current and emerging therapies to combat persistent intracellular pathogens. Curr. Opin. Pharmacol. 48, 33–39 (2019).

    CAS  PubMed  Google Scholar 

  2. Tenter, A. M., Heckeroth, A. R. & Weiss, L. M. Toxoplasma gondii: from animals to humans. Int. J. Parasitol. 30, 1217–1258 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Taylor, S. et al. A secreted serine-threonine kinase determines virulence in the eukaryotic pathogen Toxoplasma gondii. Science 314, 1776–1780 (2006).

    CAS  PubMed  Google Scholar 

  4. Saeij, J. P. et al. Polymorphic secreted kinases are key virulence factors in toxoplasmosis. Science 314, 1780–1783 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Ben Chaabene, R., Lentini, G. & Soldati-Favre, D. Biogenesis and discharge of the rhoptries: key organelles for entry and hijack of host cells by the Apicomplexa. Mol. Microbiol. 115, 453–465 (2021).

    PubMed  Google Scholar 

  7. Cova, M. M., Lamarque, M. H. & Lebrun, M. How Apicomplexa parasites secrete and build their invasion machinery. Annu. Rev. Microbiol. 76, 619–640 (2022).

    CAS  PubMed  Google Scholar 

  8. Sasai, M. & Yamamoto, M. Anti-Toxoplasma host defense systems and the parasitic counterdefense mechanisms. Parasitol. Int. 89, 102593 (2022).

    CAS  PubMed  Google Scholar 

  9. Denkers, E. Y., Bzik, D. J., Fox, B. A. & Butcher, B. A. An inside job: hacking into Janus kinase/signal transducer and activator of transcription signaling cascades by the intracellular protozoan Toxoplasma gondii. Infect. Immun. 80, 476–482 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Boothroyd, J. C. & Dubremetz, J. F. Kiss and spit: the dual roles of Toxoplasma rhoptries. Nat. Rev. Microbiol. 6, 79–88 (2008).

    CAS  PubMed  Google Scholar 

  11. Bradley, P. J. & Sibley, L. D. Rhoptries: an arsenal of secreted virulence factors. Curr. Opin. Microbiol. 10, 582–587 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Gazzinelli, R. T., Mendonca-Neto, R., Lilue, J., Howard, J. & Sher, A. Innate resistance against Toxoplasma gondii: an evolutionary tale of mice, cats, and men. Cell Host Microbe 15, 132–138 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Haldar, A. K. et al. Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins. Proc. Natl Acad. Sci. USA 112, E5628–E5637 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Haldar, A. K. et al. IRG and GBP host resistance factors target aberrant, ‘non-self’ vacuoles characterized by the missing of ‘self’ IRGM proteins. PLoS Pathog. 9, e1003414 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Virreira Winter, S. et al. Determinants of GBP recruitment to Toxoplasma gondii vacuoles and the parasitic factors that control it. PLoS ONE 6, e24434 (2011).

    PubMed  PubMed Central  Google Scholar 

  16. Khaminets, A. et al. Coordinated loading of IRG resistance GTPases on to the Toxoplasma gondii parasitophorous vacuole. Cell Microbiol. 12, 939–961 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Fentress, S. J. et al. Phosphorylation of immunity-related GTPases by a Toxoplasma gondii-secreted kinase promotes macrophage survival and virulence. Cell Host Microbe 8, 484–495 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Steinfeldt, T. et al. Phosphorylation of mouse immunity-related GTPase (IRG) resistance proteins is an evasion strategy for virulent Toxoplasma gondii. PLoS Biol. 8, e1000576 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Niedelman, W. et al. The rhoptry proteins ROP18 and ROP5 mediate Toxoplasma gondii evasion of the murine, but not the human, interferon-gamma response. PLoS Pathog. 8, e1002784 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Reese, M. L., Shah, N. & Boothroyd, J. C. The Toxoplasma pseudokinase ROP5 is an allosteric inhibitor of the immunity-related GTPases. J. Biol. Chem. 289, 27849–27858 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Fleckenstein, M. C. et al. A Toxoplasma gondii pseudokinase inhibits host IRG resistance proteins. PLoS Biol. 10, e1001358 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Behnke, M. S. et al. The polymorphic pseudokinase ROP5 controls virulence in Toxoplasma gondii by regulating the active kinase ROP18. PLoS Pathog. 8, e1002992 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Etheridge, R. D. et al. The Toxoplasma pseudokinase ROP5 forms complexes with ROP18 and ROP17 kinases that synergize to control acute virulence in mice. Cell Host Microbe 15, 537–550 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Yamamoto, M. et al. A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3. J. Exp. Med. 206, 2747–2760 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ong, Y. C., Reese, M. L. & Boothroyd, J. C. Toxoplasma rhoptry protein 16 (ROP16) subverts host function by direct tyrosine phosphorylation of STAT6. J. Biol. Chem. 285, 28731–28740 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Boyle, J. P., Saeij, J. P., Harada, S. Y., Ajioka, J. W. & Boothroyd, J. C. Expression quantitative trait locus mapping of Toxoplasma genes reveals multiple mechanisms for strain-specific differences in gene expression. Eukaryot. Cell 7, 1403–1414 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Jensen, K. D. et al. Toxoplasma polymorphic effectors determine macrophage polarization and intestinal inflammation. Cell Host Microbe 9, 472–483 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Krishnamurthy, S. et al. CRISPR screens identify Toxoplasma genes that determine parasite fitness in interferon gamma-stimulated human cells. mBio 14, e0006023 (2023).

    PubMed  Google Scholar 

  29. Wang, Y. et al. Genome-wide screens identify Toxoplasma gondii determinants of parasite fitness in IFNγ-activated murine macrophages. Nat. Commun. 11, 5258 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Young, J. et al. A CRISPR platform for targeted in vivo screens identifies Toxoplasma gondii virulence factors in mice. Nat. Commun. 10, 3963 (2019).

    PubMed  PubMed Central  Google Scholar 

  31. Sangare, L. O. et al. In vivo CRISPR screen identifies TgWIP as a Toxoplasma modulator of dendritic cell migration. Cell Host Microbe 26, 478–492 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Butterworth, S. et al. Toxoplasma gondii virulence factor ROP1 reduces parasite susceptibility to murine and human innate immune restriction. PLoS Pathog. 18, e1011021 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Butterworth, S. et al. High-throughput identification of Toxoplasma gondii effector proteins that target host cell transcription. Cell Host Microbe 31, 1748–1762 (2023).

    CAS  PubMed  Google Scholar 

  34. Mageswaran, S. K. et al. In situ ultrastructures of two evolutionarily distant apicomplexan rhoptry secretion systems. Nat. Commun. 12, 4983 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Segev-Zarko, L. A. et al. Cryo-electron tomography with mixed-scale dense neural networks reveals key steps in deployment of Toxoplasma invasion machinery. PNAS Nexus 1, pgac183 (2022).

    PubMed  PubMed Central  Google Scholar 

  36. Aquilini, E. et al. An Alveolata secretory machinery adapted to parasite host cell invasion. Nat. Microbiol 6, 425–434 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Koshy, A. A. et al. Toxoplasma co-opts host cells it does not invade. PLoS Pathog. 8, e1002825 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Cabral, C. M. et al. Neurons are the primary target cell for the brain-tropic intracellular parasite Toxoplasma gondii. PLoS Pathog. 12, e1005447 (2016).

    PubMed  PubMed Central  Google Scholar 

  39. Bougdour, A. et al. Host cell subversion by Toxoplasma GRA16, an exported dense granule protein that targets the host cell nucleus and alters gene expression. Cell Host Microbe 13, 489–500 (2013).

    CAS  PubMed  Google Scholar 

  40. Gay, G. et al. Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses. J. Exp. Med. 213, 1779–1798 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Olias, P., Etheridge, R. D., Zhang, Y., Holtzman, M. J. & Sibley, L. D. Toxoplasma effector recruits the Mi-2/NuRD complex to repress STAT1 transcription and block IFN-γ-dependent gene expression. Cell Host Microbe 20, 72–82 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Braun, L. et al. A Toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation. J. Exp. Med. 210, 2071–2086 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. He, H. et al. Characterization of a Toxoplasma effector uncovers an alternative GSK3/β-catenin-regulatory pathway of inflammation. eLife https://doi.org/10.7554/eLife.39887 (2018).

  44. Rosenberg, A. & Sibley, L. D. Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis. Cell Host Microbe 29, 1186–1198 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Tomita, T. et al. Toxoplasma gondii matrix antigen 1 is a secreted immunomodulatory effector. mBio https://doi.org/10.1128/mBio.00603-21 (2021).

  46. Ma, J. S. et al. Selective and strain-specific NFAT4 activation by the Toxoplasma gondii polymorphic dense granule protein GRA6. J. Exp. Med. 211, 2013–2032 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ten Hoeve, A. L. et al. The Toxoplasma effector GRA28 promotes parasite dissemination by inducing dendritic cell-like migratory properties in infected macrophages. Cell Host Microbe 30, 1570–1588 (2022).

    PubMed  PubMed Central  Google Scholar 

  48. Alaganan, A., Fentress, S. J., Tang, K., Wang, Q. & Sibley, L. D. Toxoplasma GRA7 effector increases turnover of immunity-related GTPases and contributes to acute virulence in the mouse. Proc. Natl Acad. Sci. USA 111, 1126–1131 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Braun, L. et al. The Toxoplasma effector TEEGR promotes parasite persistence by modulating NF-κB signalling via EZH2. Nat. Microbiol. 4, 1208–1220 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Panas, M. W., Naor, A., Cygan, A. M. & Boothroyd, J. C. Toxoplasma controls host cyclin E expression through the use of a novel MYR1-dependent effector protein, HCE1. mBio https://doi.org/10.1128/mBio.00674-19 (2019).

  51. Tomita, T., Guevara, R. B., Shah, L. M., Afrifa, A. Y. & Weiss, L. M. Secreted effectors modulating immune responses to Toxoplasma gondii. Life https://doi.org/10.3390/life11090988 (2021).

  52. Panas, M. W. & Boothroyd, J. C. Seizing control: How dense granule effector proteins enable Toxoplasma to take charge. Mol. Microbiol. 115, 466–477 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hakimi, M. A. Epigenetic reprogramming in host–parasite coevolution: the Toxoplasma paradigm. Annu Rev. Microbiol. 76, 135–155 (2022).

    CAS  PubMed  Google Scholar 

  54. Marti, M., Good, R. T., Rug, M., Knuepfer, E. & Cowman, A. F. Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306, 1930–1933 (2004).

    CAS  PubMed  Google Scholar 

  55. Hiller, N. L. et al. A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306, 1934–1937 (2004).

    CAS  PubMed  Google Scholar 

  56. Chang, H. H. et al. N-terminal processing of proteins exported by malaria parasites. Mol. Biochem. Parasitol. 160, 107–115 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Boddey, J. A. et al. An aspartyl protease directs malaria effector proteins to the host cell. Nature 463, 627–631 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Boddey, J. A., Moritz, R. L., Simpson, R. J. & Cowman, A. F. Role of the Plasmodium export element in trafficking parasite proteins to the infected erythrocyte. Traffic 10, 285–299 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Dogga, S. K. et al. A druggable secretory protein maturase of Toxoplasma essential for invasion and egress. eLife https://doi.org/10.7554/eLife.27480 (2017).

  60. Pelle, K. G. et al. Shared elements of host-targeting pathways among apicomplexan parasites of differing lifestyles. Cell Microbiol. 17, 1618–1639 (2015).

    CAS  PubMed  Google Scholar 

  61. Coffey, M. J. et al. An aspartyl protease defines a novel pathway for export of Toxoplasma proteins into the host cell. eLife https://doi.org/10.7554/eLife.10809 (2015).

  62. Hammoudi, P. M. et al. Fundamental roles of the Golgi-associated Toxoplasma aspartyl protease, ASP5, at the host–parasite interface. PLoS Pathog. 11, e1005211 (2015).

    PubMed  PubMed Central  Google Scholar 

  63. Curt-Varesano, A., Braun, L., Ranquet, C., Hakimi, M. A. & Bougdour, A. The aspartyl protease TgASP5 mediates the export of the Toxoplasma GRA16 and GRA24 effectors into host cells. Cell Microbiol. 18, 151–167 (2016).

    CAS  PubMed  Google Scholar 

  64. Coffey, M. J. et al. Aspartyl protease 5 matures dense granule proteins that reside at the host–parasite interface in Toxoplasma gondii. mBio https://doi.org/10.1128/mBio.01796-18 (2018).

  65. de Koning-Ward, T. F., Dixon, M. W., Tilley, L. & Gilson, P. R. Plasmodium species: master renovators of their host cells. Nat. Rev. Microbiol. 14, 494–507 (2016).

    PubMed  Google Scholar 

  66. Marapana, D. S. et al. Plasmepsin V cleaves malaria effector proteins in a distinct endoplasmic reticulum translocation interactome for export to the erythrocyte. Nat. Microbiol. 3, 1010–1022 (2018).

    CAS  PubMed  Google Scholar 

  67. Franco, M. et al. A novel secreted protein, MYR1, is central to Toxoplasma’s manipulation of host cells. mBio 7, e02231-15 (2016).

    PubMed  PubMed Central  Google Scholar 

  68. Cygan, A. M. et al. Coimmunoprecipitation with MYR1 identifies three additional proteins within the Toxoplasma gondii parasitophorous vacuole required for translocation of dense granule effectors into host cells. mSphere https://doi.org/10.1128/mSphere.00858-19 (2020).

  69. Marino, N. D. et al. Identification of a novel protein complex essential for effector translocation across the parasitophorous vacuole membrane of Toxoplasma gondii. PLoS Pathog. 14, e1006828 (2018).

    PubMed  PubMed Central  Google Scholar 

  70. Beck, J. R., Muralidharan, V., Oksman, A. & Goldberg, D. E. PTEX component HSP101 mediates export of diverse malaria effectors into host erythrocytes. Nature 511, 592–595 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Elsworth, B. et al. PTEX is an essential nexus for protein export in malaria parasites. Nature 511, 587–591 (2014).

    CAS  PubMed  Google Scholar 

  72. de Koning-Ward, T. F. et al. A newly discovered protein export machine in malaria parasites. Nature 459, 945–949 (2009).

    PubMed  PubMed Central  Google Scholar 

  73. Ho, C. M. et al. Malaria parasite translocon structure and mechanism of effector export. Nature 561, 70–75 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Gold, D. A. et al. The Toxoplasma dense granule proteins GRA17 and GRA23 mediate the movement of small molecules between the host and the parasitophorous vacuole. Cell Host Microbe 17, 642–652 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Blakely, W. J., Holmes, M. J. & Arrizabalaga, G. The secreted acid phosphatase domain-containing GRA44 from Toxoplasma gondii is required for c-Myc induction in infected cells. mSphere https://doi.org/10.1128/mSphere.00877-19 (2020).

  76. Zhao, Y. G. & Zhang, H. Phase separation in membrane biology: the interplay between membrane-bound organelles and membraneless condensates. Dev. Cell 55, 30–44 (2020).

    CAS  PubMed  Google Scholar 

  77. Treeck, M., Sanders, J. L., Elias, J. E. & Boothroyd, J. C. The phosphoproteomes of Plasmodium falciparum and Toxoplasma gondii reveal unusual adaptations within and beyond the parasites’ boundaries. Cell Host Microbe 10, 410–419 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Panas, M. W. et al. Translocation of dense granule effectors across the parasitophorous vacuole membrane in Toxoplasma-infected cells requires the activity of ROP17, a rhoptry protein kinase. mSphere https://doi.org/10.1128/mSphere.00276-19 (2019).

  79. Drewry, L. L. et al. The secreted kinase ROP17 promotes Toxoplasma gondii dissemination by hijacking monocyte tissue migration. Nat. Microbiol. 4, 1951–1963 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Nadipuram, S. M. et al. In vivo biotinylation of the Toxoplasma parasitophorous vacuole reveals novel dense granule proteins important for parasite growth and pathogenesis. mBio https://doi.org/10.1128/mBio.00808-16 (2016).

  81. Mayoral, J. et al. Toxoplasma gondii PPM3C, a secreted protein phosphatase, affects parasitophorous vacuole effector export. PLoS Pathog. 16, e1008771 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Naor, A. et al. MYR1-dependent effectors are the major drivers of a host cell’s early response to Toxoplasma, including counteracting MYR1-independent effects. mBio https://doi.org/10.1128/mBio.02401-17 (2018).

  83. Rastogi, S., Xue, Y., Quake, S. R. & Boothroyd, J. C. Differential impacts on host transcription by ROP and GRA effectors from the intracellular parasite Toxoplasma gondii. mBio https://doi.org/10.1128/mBio.00182-20 (2020).

  84. Chen, L. et al. The Toxoplasma gondii virulence factor ROP16 acts in cis and trans, and suppresses T cell responses. J. Exp. Med. https://doi.org/10.1084/jem.20181757 (2020).

  85. Fouts, A. E. & Boothroyd, J. C. Infection with Toxoplasma gondii bradyzoites has a diminished impact on host transcript levels relative to tachyzoite infection. Infect. Immun. 75, 634–642 (2007).

    CAS  PubMed  Google Scholar 

  86. Seizova, S. et al. Transcriptional modification of host cells harboring Toxoplasma gondii bradyzoites prevents IFN gamma-mediated cell death. Cell Host Microbe 30, 232–247 (2022).

    CAS  PubMed  Google Scholar 

  87. Sugi, T. et al. Single cell transcriptomes of in vitro bradyzoite infected cells reveals Toxoplasma gondii stage dependent host cell alterations. Front. Cell Infect. Microbiol. 12, 848693 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Rahman, M. T. et al. The redox homeostasis of skeletal muscle cells regulates stage differentiation of Toxoplasma gondii. Front Cell Infect. Microbiol. 11, 798549 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Swierzy, I. J. et al. Divergent co-transcriptomes of different host cells infected with Toxoplasma gondii reveal cell type-specific host–parasite interactions. Sci. Rep. 7, 7229 (2017).

    PubMed  PubMed Central  Google Scholar 

  90. Christiansen, C. et al. In vitro maturation of Toxoplasma gondii bradyzoites in human myotubes and their metabolomic characterization. Nat. Commun. 13, 1168 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Waldman, B. S. et al. Identification of a master regulator of differentiation in Toxoplasma. Cell 180, 359–372 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Lemgruber, L., Lupetti, P., Martins-Duarte, E. S., De Souza, W. & Vommaro, R. C. The organization of the wall filaments and characterization of the matrix structures of Toxoplasma gondii cyst form. Cell Microbiol. 13, 1920–1932 (2011).

    CAS  PubMed  Google Scholar 

  93. Kannan, G., Thaprawat, P., Schultz, T. L. & Carruthers, V. B. Acquisition of host cytosolic protein by Toxoplasma gondii bradyzoites. mSphere https://doi.org/10.1128/mSphere.00934-20 (2021).

  94. Paredes-Santos, T., Wang, Y., Waldman, B., Lourido, S. & Saeij, J. P. The GRA17 parasitophorous vacuole membrane permeability pore contributes to bradyzoite viability. Front. Cell Infect. Microbiol. 9, 321 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Tu, V. et al. Enrichment and proteomic characterization of the cyst wall from in vitro Toxoplasma gondii cysts. mBio https://doi.org/10.1128/mBio.00469-19 (2019).

  96. Krishnamurthy, S. & Saeij, J. P. J. Toxoplasma does not secrete the GRA16 and GRA24 effectors beyond the parasitophorous vacuole membrane of tissue cysts. Front. Cell Infect. Microbiol. 8, 366 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Dogga, S. K. et al. Importance of aspartyl protease 5 in the establishment of the intracellular niche during acute and chronic infection of Toxoplasma gondii. Mol. Microbiol. 118, 601–622 (2022).

    CAS  PubMed  Google Scholar 

  98. Mayoral, J., Shamamian, P. Jr & Weiss, L. M. In vitro characterization of protein effector export in the bradyzoite stage of Toxoplasma gondii. mBio https://doi.org/10.1128/mBio.00046-20 (2020).

  99. Fritz, H. M. et al. Transcriptomic analysis of Toxoplasma development reveals many novel functions and structures specific to sporozoites and oocysts. PLoS ONE 7, e29998 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Guiton, P. S., Sagawa, J. M., Fritz, H. M. & Boothroyd, J. C. An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-κB-like signature in infected host cells. PLoS ONE 12, e0173018 (2017).

    PubMed  PubMed Central  Google Scholar 

  101. Ramakrishnan, C. et al. An experimental genetically attenuated live vaccine to prevent transmission of Toxoplasma gondii by cats. Sci. Rep. 9, 1474 (2019).

    PubMed  PubMed Central  Google Scholar 

  102. Fritz, H. M., Bowyer, P. W., Bogyo, M., Conrad, P. A. & Boothroyd, J. C. Proteomic analysis of fractionated Toxoplasma oocysts reveals clues to their environmental resistance. PLoS ONE 7, e29955 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Possenti, A. et al. Global proteomic analysis of the oocyst/sporozoite of Toxoplasma gondii reveals commitment to a host-independent lifestyle. BMC Genom. 14, 183 (2013).

    CAS  Google Scholar 

  104. Hehl, A. B. et al. Asexual expansion of Toxoplasma gondii merozoites is distinct from tachyzoites and entails expression of non-overlapping gene families to attach, invade, and replicate within feline enterocytes. BMC Genom. 16, 66 (2015).

    Google Scholar 

  105. Martorelli Di Genova, B., Wilson, S. K., Dubey, J. P. & Knoll, L. J. Intestinal delta-6-desaturase activity determines host range for Toxoplasma sexual reproduction. PLoS Biol. 17, e3000364 (2019).

    PubMed  PubMed Central  Google Scholar 

  106. Rosowski, E. E. et al. Strain-specific activation of the NF-κB pathway by GRA15, a novel Toxoplasma gondii dense granule protein. J. Exp. Med. 208, 195–212 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank our funding sources, The National Health and Medical Research Council (NHMRC) of Australia (GNT2012271) to C.J.T. J.B. acknowledges The National Institutes of Health (NIH) USA (R01AI172823) and the Chan-Zuckerberg Biohub. A.F. was supported by a NIH T32 training grant and a Howard Hughes Medical Institute (HHMI) Gilliam Fellowship. We thank the past and present members of our respective groups who contributed much of the data and many of the ideas discussed here.

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  1. School of Life Sciences, The University of Dundee, Dundee, UK

    Simona Seizova

  2. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA, USA

    Abel Ferrel & John Boothroyd

  3. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

    Christopher J. Tonkin

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  1. Simona Seizova
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S.S., A.F., J.B. and C.J.T. conceived and wrote the original draft and edited the paper. S.S. and C.J.T. prepared the figures.

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Correspondence to John Boothroyd or Christopher J. Tonkin.

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Seizova, S., Ferrel, A., Boothroyd, J. et al. Toxoplasma protein export and effector function. Nat Microbiol 9, 17–28 (2024). https://doi.org/10.1038/s41564-023-01563-z

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