A latent ability to persist: differentiation in Toxoplasma gondii

Cellular and Molecular Life Sciences volume 75, pages2355–2373(2018)Cite this article

Abstract

A critical factor in the transmission and pathogenesis of Toxoplasma gondii is the ability to convert from an acute disease-causing, proliferative stage (tachyzoite), to a chronic, dormant stage (bradyzoite). The conversion of the tachyzoite-containing parasitophorous vacuole membrane into the less permeable bradyzoite cyst wall allows the parasite to persist for years within the host to maximize transmissibility to both primary (felids) and secondary (virtually all other warm-blooded vertebrates) hosts. This review presents our current understanding of the latent stage, including the factors that are important in bradyzoite induction and maintenance. Also discussed are the recent studies that have begun to unravel the mechanisms behind stage switching.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

US$ 39.95

Tax calculation will be finalised during checkout.

Fig. 1

References

  1. 1.

    Hutchison WM, Dunachie JF, Siim JC, Work K (1969) Life cycle of Toxoplasma gondii. BMJ 4:806

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. 2.

    Tenter AM, Heckeroth AR, Weiss LM (2000) Toxoplasma gondii: from animals to humans. Int J Parasitol 30:1217–1258

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  3. 3.

    Sullivan WJ Jr, Jeffers V (2012) Mechanisms of Toxoplasma gondii persistence and latency. FEMS Microbiol Rev 36:717–733

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Luft BJ, Remington JS (1988) AIDS commentary, Toxoplasmic encephalitis. J Infect Dis 157:1–6

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    McLeod R, Mack D, Brown C (1991) Toxoplasma gondii—new advances in cellular and molecular biology. Exp Parasitol 72:109–121

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Wong SY, Remington JS (1993) Biology of Toxoplasma gondii. AIDS 7:299–316

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Luft BJ, Brooks RG, Conley FK, McCabe RE, Remington JS (1984) Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. J Am Med Assoc 252:913–917

    Article  CAS  Google Scholar 

  8. 8.

    Dubey JP (1998) Advances in the life cycle of Toxoplasma gondii. Int J Parasitol 28:1019–1024

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Jones J, Lopez A, Wilson M (2003) Congenital toxoplasmosis. Am Fam Physician 67:2131–2138

    PubMed  Google Scholar 

  10. 10.

    Wallace GR, Stanford MR (2008) Immunity and Toxoplasma retinochoroiditis. Clin Exp Immunol 153:309–315

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Vasconcelos-Santos DV (2012) Ocular manifestations of systemic disease: toxoplasmosis. Curr Opin Ophthalmol 23:543–550

    PubMed  Article  Google Scholar 

  12. 12.

    Bowie WR, King AS, Werker DH, Isaac-Renton JL, Bell A, Eng SB, Marion SA (1997) Outbreak of toxoplasmosis associated with municipal drinking water. The BC Toxoplasma Investigation Team. Lancet 350:173–177

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Aramini JJ, Stephen C, Dubey JP, Engelstoft C, Schwantje H, Ribble CS (1999) Potential contamination of drinking water with Toxoplasma gondii oocysts. Epidemiol Infect 122:305–315

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Miller MA, Gardner IA, Kreuder C, Paradies DM, Worcester KR, Jessup DA, Dodd E, Harris MD, Ames JA, Packham AE, Conrad PA (2002) Coastal freshwater runoff is a risk factor for Toxoplasma gondii infection of southern sea otters (Enhydra lutris nereis). Int J Parasitol 32:997–1006

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Ferguson DJ, Hutchison WM (1987) The host-parasite relationship of Toxoplasma gondii in the brains of chronically infected mice. Virchows Archiv A Pathol Anat Histopathol 411:39–43

    Article  CAS  Google Scholar 

  16. 16.

    Ferguson DJ, Hutchison WM (1987) An ultrastructural study of the early development and tissue cyst formation of Toxoplasma gondii in the brains of mice. Parasitol Res 73:483–491

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Ferguson DJ, Hutchison WM, Pettersen E (1989) Tissue cyst rupture in mice chronically infected with Toxoplasma gondii. An immunocytochemical and ultrastructural study. Parasitol Res 75:599–603

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Cabral CM, Tuladhar S, Dietrich HK, Nguyen E, MacDonald WR, Trivedi T, Devineni A, Koshy AA (2016) Neurons are the primary target cell for the brain-tropic intracellular parasite Toxoplasma gondii. PLoS Pathog 12:e1005447

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Koshy AA, Dietrich HK, Christian DA, Melehani JH, Shastri AJ, Hunter CA, Boothroyd JC (2012) Toxoplasma co-opts host cells it does not invade. PLoS Pathog 8:e1002825

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Kim K, Weiss LM (2004) Toxoplasma gondii: the model apicomplexan. Int J Parasitol 34:423–432

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    Soete M, Dubremetz JF (1996) Toxoplasma gondii: kinetics of stage-specific protein expression during tachyzoite-bradyzoite conversion in vitro. Curr Top Microbiol Immunol 219:76–80

    PubMed  CAS  Google Scholar 

  22. 22.

    Dzierszinski F, Nishi M, Ouko L, Roos DS (2004) Dynamics of Toxoplasma gondii differentiation. Eukaryot Cell 3:992–1003

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Lane A, Soete M, Dubremetz JF, Smith JE (1996) Toxoplasma gondii: appearance of specific markers during the development of tissue cysts in vitro. Parasitol Res 82:340–346

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Di Cristina M, Marocco D, Galizi R, Proietti C, Spaccapelo R, Crisanti A (2008) Temporal and spatial distribution of Toxoplasma gondii differentiation into Bradyzoites and tissue cyst formation in vivo. Infect Immun 76:3491–3501

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    van der Waaij D (1959) Formation, growth and multiplication of Toxoplasma gondii cysts in mouse brain. Trop Geogr Med 11:345–360

    Google Scholar 

  26. 26.

    Mehlhorn H, Frenkel JK (1980) Ultrastructural comparison of cysts and zoites of Toxoplasma gondii, Sarcocystis muris, and Hammondia hammondi in skeletal muscle of mice. J Parasitol 66:59–67

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Weiss LM, Kim K (2000) The development and biology of bradyzoites of Toxoplasma gondii. Front Biosci J Virtual Libr 5:D391–D405

    Article  CAS  Google Scholar 

  28. 28.

    Tomita T, Bzik DJ, Ma YF, Fox BA, Markillie LM, Taylor RC, Kim K, Weiss LM (2013) The Toxoplasma gondii cyst wall protein CST1 is critical for cyst wall integrity and promotes bradyzoite persistence. PLoS Pathog 9:e1003823

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Wang J, Dixon SE, Ting LM, Liu TK, Jeffers V, Croken MM, Calloway M, Cannella D, Hakimi MA, Kim K, Sullivan WJ Jr (2014) Lysine acetyltransferase GCN5b interacts with AP2 factors and is required for Toxoplasma gondii proliferation. PLoS Pathog 10:e1003830

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Watts E, Zhao Y, Dhara A, Eller B, Patwardhan A, Sinai AP (2015) Novel approaches reveal that Toxoplasma gondii bradyzoites within tissue cysts are dynamic and replicating entities in vivo. mBio 6:e01155–e01215

  31. 31.

    Wang T, Gao JM, Yi SQ, Geng GQ, Gao XJ, Shen JL, Lu FL, Wen YZ, Hide G, Lun ZR (2014) Toxoplasma gondii infection in the peritoneal macrophages of rats treated with glucocorticoids. Parasitol Res 113:351–358

    PubMed  Article  Google Scholar 

  32. 32.

    Knoll LJ, Boothroyd JC (1998) Molecular biology’s lessons about toxoplasma development: stage-specific homologs. Parasitol Today 14:490–493

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Zhang YW, Halonen SK, Ma YF, Wittner M, Weiss LM (2001) Initial characterization of CST1, a Toxoplasma gondii cyst wall glycoprotein. Infect Immun 69:501–507

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Ferguson DJ (2004) Use of molecular and ultrastructural markers to evaluate stage conversion of Toxoplasma gondii in both the intermediate and definitive host. Int J Parasitol 34:347–360

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Torpier G, Charif H, Darcy F, Liu J, Darde ML, Capron A (1993) Toxoplasma gondii: differential location of antigens secreted from encysted bradyzoites. Exp Parasitol 77:13–22

    PubMed  Article  CAS  Google Scholar 

  36. 36.

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

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Parmley SF, Yang S, Harth G, Sibley LD, Sucharczuk A, Remington JS (1994) Molecular characterization of a 65-kilodalton Toxoplasma gondii antigen expressed abundantly in the matrix of tissue cysts. Mol Biochem Parasitol 66:283–296

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Parmley S, Slifer T, Araujo F (2002) Protective effects of immunization with a recombinant cyst antigen in mouse models of infection with Toxoplasma gondii tissue cysts. J Infect Dis 185(Suppl 1):S90–S95

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Buchholz KR, Bowyer PW, Boothroyd JC (2013) Bradyzoite pseudokinase 1 is crucial for efficient oral infectivity of the Toxoplasma gondii tissue cyst. Eukaryot Cell 12:399–410

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Buchholz KR, Fritz HM, Chen X, Durbin-Johnson B, Rocke DM, Ferguson DJ, Conrad PA, Boothroyd JC (2011) Identification of tissue cyst wall components by transcriptome analysis of in vivo and in vitro Toxoplasma gondii bradyzoites. Eukaryot Cell 10:1637–1647

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    Craver MP, Rooney PJ, Knoll LJ (2010) Isolation of Toxoplasma gondii development mutants identifies a potential proteophosphogylcan that enhances cyst wall formation. Mol Biochem Parasitol 169:120–123

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Tomavo S, Fortier B, Soete M, Ansel C, Camus D, Dubremetz JF (1991) Characterization of bradyzoite-specific antigens of Toxoplasma gondii. Infect Immun 59:3750–3753

    PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Bohne W, Gross U, Ferguson DJ, Heesemann J (1995) Cloning and characterization of a bradyzoite-specifically expressed gene (hsp30/bag1) of Toxoplasma gondii, related to genes encoding small heat-shock proteins of plants. Mol Microbiol 16:1221–1230

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Bohne W, Parmley SF, Yang S, Gross U (1996) Bradyzoite-specific genes. Curr Top Microbiol Immunol 219:81–91

    PubMed  CAS  Google Scholar 

  45. 45.

    Parmley SF, Weiss LM, Yang S (1995) Cloning of a bradyzoite-specific gene of Toxoplasma gondii encoding a cytoplasmic antigen. Mol Biochem Parasitol 73:253–257

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Yang S, Parmley SF (1995) A bradyzoite stage-specifically expressed gene of Toxoplasma gondii encodes a polypeptide homologous to lactate dehydrogenase. Mol Biochem Parasitol 73:291–294

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Yang S, Parmley SF (1997) Toxoplasma gondii expresses two distinct lactate dehydrogenase homologous genes during its life cycle in intermediate hosts. Gene 184:1–12

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Denton H, Roberts CW, Alexander J, Thong KW, Coombs GH (1996) Enzymes of energy metabolism in the bradyzoites and tachyzoites of Toxoplasma gondii. FEMS Microbiol Lett 137:103–108

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Yahiaoui B, Dzierszinski F, Bernigaud A, Slomianny C, Camus D, Tomavo S (1999) Isolation and characterization of a subtractive library enriched for developmentally regulated transcripts expressed during encystation of Toxoplasma gondii. Mol Biochem Parasitol 99:223–235

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Toursel C, Dzierszinski F, Bernigaud A, Mortuaire M, Tomavo S (2000) Molecular cloning, organellar targeting and developmental expression of mitochondrial chaperone HSP60 in Toxoplasma gondii. Mol Biochem Parasitol 111:319–332

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Holpert M, Luder CG, Gross U, Bohne W (2001) Bradyzoite-specific expression of a P-type ATPase in Toxoplasma gondii. Mol Biochem Parasitol 112:293–296

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Odberg-Ferragut C, Soete M, Engels A, Samyn B, Loyens A, Van Beeumen J, Camus D, Dubremetz JF (1996) Molecular cloning of the Toxoplasma gondii sag4 gene encoding an 18 kDa bradyzoite specific surface protein. Mol Biochem Parasitol 82:237–244

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Manger ID, Hehl A, Parmley S, Sibley LD, Marra M, Hillier L, Waterston R, Boothroyd JC (1998) Expressed sequence tag analysis of the bradyzoite stage of Toxoplasma gondii: identification of developmentally regulated genes. Infect Immun 66:1632–1637

    PubMed  PubMed Central  CAS  Google Scholar 

  54. 54.

    Bohne W, Wirsing A, Gross U (1997) Bradyzoite-specific gene expression in Toxoplasma gondii requires minimal genomic elements. Mol Biochem Parasitol 85:89–98

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Knoll LJ, Boothroyd JC (1998) Isolation of developmentally regulated genes from Toxoplasma gondii by a gene trap with the positive and negative selectable marker hypoxanthine–xanthine–guanine phosphoribosyltransferase. Mol Cell Biol 18:807–814

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56.

    Pittman KJ, Aliota MT, Knoll LJ (2014) Dual transcriptional profiling of mice and Toxoplasma gondii during acute and chronic infection. BMC Genom 15:806

    Article  CAS  Google Scholar 

  57. 57.

    Zhang YW, Kim K, Ma YF, Wittner M, Tanowitz HB, Weiss LM (1999) Disruption of the Toxoplasma gondii bradyzoite-specific gene BAG1 decreases in vivo cyst formation. Mol Microbiol 31:691–701

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Bohne W, Hunter CA, White MW, Ferguson DJ, Gross U, Roos DS (1998) Targeted disruption of the bradyzoite-specific gene BAG1 does not prevent tissue cyst formation in Toxoplasma gondii. Mol Biochem Parasitol 92:291–301

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Holpert M, Gross U, Bohne W (2006) Disruption of the bradyzoite-specific P-type (H+)-ATPase PMA1 in Toxoplasma gondii leads to decreased bradyzoite differentiation after stress stimuli but does not interfere with mature tissue cyst formation. Mol Biochem Parasitol 146:129–133

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Kim SK, Fouts AE, Boothroyd JC (2007) Toxoplasma gondii dysregulates IFN-gamma-inducible gene expression in human fibroblasts: insights from a genome-wide transcriptional profiling. J Immunol 178:5154–5165

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Fox BA, Falla A, Rommereim LM, Tomita T, Gigley JP, Mercier C, Cesbron-Delauw MF, Weiss LM, Bzik DJ (2011) Type II Toxoplasma gondii KU80 knockout strains enable functional analysis of genes required for cyst development and latent infection. Eukaryot Cell 10:1193–1206

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Radke JB, Lucas O, De Silva EK, Ma Y, Sullivan WJ Jr, Weiss LM, Llinas M, White MW (2013) ApiAP2 transcription factor restricts development of the Toxoplasma tissue cyst. Proc Natl Acad Sci USA 110:6871–6876

    PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Walker R, Gissot M, Croken MM, Huot L, Hot D, Kim K, Tomavo S (2013) The Toxoplasma nuclear factor TgAP2XI-4 controls bradyzoite gene expression and cyst formation. Mol Microbiol 87:641–655

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Huang S, Holmes MJ, Radke JB, Hong DP, Liu TK, White MW, Sullivan WJ (2017) Toxoplasma gondii AP2IX-4 regulates gene expression during bradyzoite development. mSphere 2:e00054–e00017

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Hong DP, Radke JB, White MW (2017) Opposing transcriptional mechanisms regulate toxoplasma development. mSphere 2:e00347–e00416

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66.

    Radke JB, Worth D, Hong DP, Huang S, Sullivan WJ, Wilson EH, White M (2017) Transcriptional repression by ApiAP2 factors is central to chronic toxoplasmosis. bioRxiv. https://doi.org/10.1101/100628

    Article  Google Scholar 

  67. 67.

    Singh U, Brewer JL, Boothroyd JC (2002) Genetic analysis of tachyzoite to bradyzoite differentiation mutants in Toxoplasma gondii reveals a hierarchy of gene induction. Mol Microbiol 44:721–733

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Matrajt M, Donald RG, Singh U, Roos DS (2002) Identification and characterization of differentiation mutants in the protozoan parasite Toxoplasma gondii. Mol Microbiol 44:735–747

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Vanchinathan P, Brewer JL, Harb OS, Boothroyd JC, Singh U (2005) Disruption of a locus encoding a nucleolar zinc finger protein decreases tachyzoite-to-bradyzoite differentiation in Toxoplasma gondii. Infect Immun 73:6680–6688

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    Anderson MZ, Brewer J, Singh U, Boothroyd JC (2009) A pseudouridine synthase homologue is critical to cellular differentiation in Toxoplasma gondii. Eukaryot Cell 8:398–409

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Frankel MB, Mordue DG, Knoll LJ (2007) Discovery of parasite virulence genes reveals a unique regulator of chromosome condensation 1 ortholog critical for efficient nuclear trafficking. Proc Natl Acad Sci USA 104:10181–10186

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Sugi T, Tu V, Ma Y, Tomita T, Weiss LM (2017) Toxoplasma gondii requires glycogen phosphorylase for balancing amylopectin storage and for efficient production of brain cysts. mBio 8:e01289–e01317

    PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Dzierszinski F, Mortuaire M, Dendouga N, Popescu O, Tomavo S (2001) Differential expression of two plant-like enolases with distinct enzymatic and antigenic properties during stage conversion of the protozoan parasite Toxoplasma gondii. J Mol Biol 309:1017–1027

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Al-Anouti F, Tomavo S, Parmley S, Ananvoranich S (2004) The expression of lactate dehydrogenase is important for the cell cycle of Toxoplasma gondii. J Biol Chem 279:52300–52311

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    Di Cristina M, Dou Z, Lunghi M, Kannan G, Huynh MH, McGovern OL, Schultz TL, Schultz AJ, Miller AJ, Hayes BM, van der Linden W, Emiliani C, Bogyo M, Besteiro S, Coppens I, Carruthers VB (2017) Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection. Nat Microbiol 2:17096

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Su C, Evans D, Cole RH, Kissinger JC, Ajioka JW, Sibley LD (2003) Recent expansion of Toxoplasma through enhanced oral transmission. Science 299:414–416

    PubMed  Article  CAS  Google Scholar 

  77. 77.

    Howe DK, Sibley LD (1995) Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease. J Infect Dis 172:1561–1566

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Barragan A, Sibley LD (2003) Migration of Toxoplasma gondii across biological barriers. Trends Microbiol 11:426–430

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Sabin AB (1938) Isolation of a filtrable, transmissible agent with “Neurolyti” properties from Toxoplasma-infected tissues. Science 88:189–191

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Soete M, Camus D, Dubremetz JF (1994) Experimental induction of bradyzoite-specific antigen expression and cyst formation by the RH strain of Toxoplasma gondii in vitro. Exp Parasitol 78:361–370

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Bohne W, Roos DS (1997) Stage-specific expression of a selectable marker in Toxoplasma gondii permits selective inhibition of either tachyzoites or bradyzoites. Mol Biochem Parasitol 88:115–126

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    Lescault PJ, Thompson AB, Patil V, Lirussi D, Burton A, Margarit J, Bond J, Matrajt M (2010) Genomic data reveal Toxoplasma gondii differentiation mutants are also impaired with respect to switching into a novel extracellular tachyzoite state. PLoS One 5:e14463

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Behnke MS, Radke JB, Smith AT, Sullivan WJ Jr, White MW (2008) The transcription of bradyzoite genes in Toxoplasma gondii is controlled by autonomous promoter elements. Mol Microbiol 68:1502–1518

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84.

    Frenkel JK, Dubey JP, Hoff RL (1976) Loss of stages after continuous passage of Toxoplasma gondii and Besnoitia jellisoni. J Protozool 23:421–424

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    Weiss LM, Ma YF, Takvorian PM, Tanowitz HB, Wittner M (1998) Bradyzoite development in Toxoplasma gondii and the hsp70 stress response. Infect Immun 66:3295–3302

    PubMed  PubMed Central  CAS  Google Scholar 

  86. 86.

    Fox BA, Gigley JP, Bzik DJ (2004) Toxoplasma gondii lacks the enzymes required for de novo arginine biosynthesis and arginine starvation triggers cyst formation. Int J Parasitol 34:323–331

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Narasimhan J, Joyce BR, Naguleswaran A, Smith AT, Livingston MR, Dixon SE, Coppens I, Wek RC, Sullivan WJ Jr (2008) Translation regulation by eukaryotic initiation factor-2 kinases in the development of latent cysts in Toxoplasma gondii. J Biol Chem 283:16591–16601

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. 88.

    Nagamune K, Hicks LM, Fux B, Brossier F, Chini EN, Sibley LD (2008) Abscisic acid controls calcium-dependent egress and development in Toxoplasma gondii. Nature 451:207–210

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Bohne W, Heesemann J, Gross U (1994) Reduced replication of Toxoplasma gondii is necessary for induction of bradyzoite-specific antigens: a possible role for nitric oxide in triggering stage conversion. Infect Immun 62:1761–1767

    PubMed  PubMed Central  CAS  Google Scholar 

  90. 90.

    Tomavo S, Boothroyd JC (1995) Interconnection between organellar functions, development and drug resistance in the protozoan parasite, Toxoplasma gondii. Int J Parasitol 25:1293–1299

    PubMed  Article  CAS  Google Scholar 

  91. 91.

    Bohne W, Heesemann J, Gross U (1993) Induction of bradyzoite-specific Toxoplasma gondii antigens in gamma interferon-treated mouse macrophages. Infect Immun 61:1141–1145

    PubMed  PubMed Central  CAS  Google Scholar 

  92. 92.

    Hartmann A, Arroyo-Olarte RD, Imkeller K, Hegemann P, Lucius R, Gupta N (2013) Optogenetic modulation of an adenylate cyclase in Toxoplasma gondii demonstrates a requirement of the parasite cAMP for host-cell invasion and stage differentiation. J Biol Chem 288:13705–13717

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. 93.

    Sugi T, Ma YF, Tomita T, Murakoshi F, Eaton MS, Yakubu R, Han B, Tu V, Kato K, Kawazu S, Gupta N, Suvorova ES, White MW, Kim K, Weiss LM (2016) Toxoplasma gondii cyclic AMP-dependent protein kinase subunit 3 is involved in the switch from tachyzoite to bradyzoite development. mBio 7:e00755–e00816

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. 94.

    Luder CGK, Rahman T (2017) Impact of the host on Toxoplasma stage differentiation. Microb Cell. 4:203–211

    PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Radke JR, Guerini MN, Jerome M, White MW (2003) A change in the premitotic period of the cell cycle is associated with bradyzoite differentiation in Toxoplasma gondii. Mol Biochem Parasitol 131:119–127

    PubMed  Article  CAS  Google Scholar 

  96. 96.

    Ihara F, Nishikawa Y (2014) Starvation of low-density lipoprotein-derived cholesterol induces bradyzoite conversion in Toxoplasma gondii. Parasit Vectors 7:248

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. 97.

    Weilhammer DR, Iavarone AT, Villegas EN, Brooks GA, Sinai AP, Sha WC (2012) Host metabolism regulates growth and differentiation of Toxoplasma gondii. Int J Parasitol 42:947–959

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Radke JR, Donald RG, Eibs A, Jerome ME, Behnke MS, Liberator P, White MW (2006) Changes in the expression of human cell division autoantigen-1 influence Toxoplasma gondii growth and development. PLoS Pathog 2:e105

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  99. 99.

    Gurnett AM, Liberator PA, Dulski PM, Salowe SP, Donald RG, Anderson JW, Wiltsie J, Diaz CA, Harris G, Chang B, Darkin-Rattray SJ, Nare B, Crumley T, Blum PS, Misura AS, Tamas T, Sardana MK, Yuan J, Biftu T, Schmatz DM (2002) Purification and molecular characterization of cGMP-dependent protein kinase from Apicomplexan parasites. A novel chemotherapeutic target. J Biol Chem 277:15913–15922

    PubMed  Article  CAS  Google Scholar 

  100. 100.

    Donald RG, Zhong T, Wiersma H, Nare B, Yao D, Lee A, Allocco J, Liberator PA (2006) Anticoccidial kinase inhibitors: identification of protein kinase targets secondary to cGMP-dependent protein kinase. Mol Biochem Parasitol 149:86–98

    PubMed  Article  CAS  Google Scholar 

  101. 101.

    McHugh TD, Gbewonyo A, Johnson JD, Holliman RE, Butcher PD (1993) Development of an in vitro model of Toxoplasma gondii cyst formation. FEMS Microbiol Lett 114:325–332

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    da Silva Ferreira, Mda F, Barbosa HS, Gross U, Luder CG (2008) Stress-related and spontaneous stage differentiation of Toxoplasma gondii. Mol BioSyst 4:824–834

    Article  CAS  Google Scholar 

  103. 103.

    Swierzy IJ, Handel U, Kaever A, Jarek M, Scharfe M, Schluter D, Luder CGK (2017) Divergent co-transcriptomes of different host cells infected with Toxoplasma gondii reveal cell type-specific host-parasite interactions. Sci Rep 7:7229

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. 104.

    Swierzy IJ, Luder CG (2015) Withdrawal of skeletal muscle cells from cell cycle progression triggers differentiation of Toxoplasma gondii towards the bradyzoite stage. Cell Microbiol 17:2–17

    PubMed  Article  CAS  Google Scholar 

  105. 105.

    Gross U, Bohne W, Soete M, Dubremetz JF (1996) Developmental differentiation between tachyzoites and bradyzoites of Toxoplasma gondii. Parasitol Today 12:30–33

    PubMed  Article  CAS  Google Scholar 

  106. 106.

    Dupont CD, Christian DA, Hunter CA (2012) Immune response and immunopathology during toxoplasmosis. Semin Immunopathol 34:793–813

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Denkers EY, Gazzinelli RT (1998) Regulation and function of T-cell-mediated immunity during Toxoplasma gondii infection. Clin Microbiol Rev 11:569–588

    PubMed  PubMed Central  CAS  Google Scholar 

  108. 108.

    Kang H, Remington JS, Suzuki Y (2000) Decreased resistance of B cell-deficient mice to infection with Toxoplasma gondii despite unimpaired expression of IFN-gamma. TNF-alpha, and inducible nitric oxide synthase. J Immunol 164:2629–2634

    PubMed  Article  CAS  Google Scholar 

  109. 109.

    Johnson LL, Sayles PC (2002) Deficient humoral responses underlie susceptibility to Toxoplasma gondii in CD4-deficient mice. Infect Immun 70:185–191

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110.

    Denkers EY, Sher A (1997) Role of natural killer and NK1+ T-cells in regulating cell-mediated immunity during Toxoplasma gondii infection. Biochem Soc Trans 25:699–703

    PubMed  Article  CAS  Google Scholar 

  111. 111.

    Lutjen S, Soltek S, Virna S, Deckert M, Schluter D (2006) Organ- and disease-stage-specific regulation of Toxoplasma gondii-specific CD8-T-cell responses by CD4 T cells. Infect Immun 74:5790–5801

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. 112.

    Combe CL, Curiel TJ, Moretto MM, Khan IA (2005) NK cells help to induce CD8(+)-T-cell immunity against Toxoplasma gondii in the absence of CD4(+) T cells. Infect Immun 73:4913–4921

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Tait ED, Jordan KA, Dupont CD, Harris TH, Gregg B, Wilson EH, Pepper M, Dzierszinski F, Roos DS, Hunter CA (2010) Virulence of Toxoplasma gondii is associated with distinct dendritic cell responses and reduced numbers of activated CD8+ T cells. J Immunol 185:1502–1512

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. 114.

    Yamamoto M, Ma JS, Mueller C, Kamiyama N, Saiga H, Kubo E, Kimura T, Okamoto T, Okuyama M, Kayama H, Nagamune K, Takashima S, Matsuura Y, Soldati-Favre D, Takeda K (2011) ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18. J Exp Med 208:1533–1546

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  115. 115.

    Suzuki Y, Orellana MA, Schreiber RD, Remington JS (1988) Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science 240:516–518

    PubMed  Article  CAS  Google Scholar 

  116. 116.

    Gazzinelli RT, Hakim FT, Hieny S, Shearer GM, Sher A (1991) Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. J Immunol 146:286–292

    PubMed  CAS  Google Scholar 

  117. 117.

    Suzuki Y, Claflin J, Wang X, Lengi A, Kikuchi T (2005) Microglia and macrophages as innate producers of interferon-gamma in the brain following infection with Toxoplasma gondii. Int J Parasitol 35:83–90

    PubMed  Article  CAS  Google Scholar 

  118. 118.

    Kang H, Suzuki Y (2001) Requirement of non-T cells that produce gamma interferon for prevention of reactivation of Toxoplasma gondii infection in the brain. Infect Immun 69:2920–2927

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. 119.

    Wang X, Suzuki Y (2007) Microglia produce IFN-gamma independently from T cells during acute toxoplasmosis in the brain. J Interf Cytokine Res 27:599–605

    Article  CAS  Google Scholar 

  120. 120.

    Scharton-Kersten TM, Wynn TA, Denkers EY, Bala S, Grunvald E, Hieny S, Gazzinelli RT, Sher A (1996) In the absence of endogenous IFN-gamma, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J Immunol 157:4045–4054

    PubMed  CAS  Google Scholar 

  121. 121.

    Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P, Trinchieri G, Sher A (1994) Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol 153:2533–2543

    PubMed  CAS  Google Scholar 

  122. 122.

    Langermans JA, van der Hulst ME, Nibbering PH, van Furth R (1992) Endogenous tumor necrosis factor alpha is required for enhanced antimicrobial activity against Toxoplasma gondii and Listeria monocytogenes in recombinant gamma interferon-treated mice. Infect Immun 60:5107–5112

    PubMed  PubMed Central  CAS  Google Scholar 

  123. 123.

    Chao CC, Anderson WR, Hu S, Gekker G, Martella A, Peterson PK (1993) Activated microglia inhibit multiplication of Toxoplasma gondii via a nitric oxide mechanism. Clin Immunol Immunopathol 67:178–183

    PubMed  Article  CAS  Google Scholar 

  124. 124.

    Peterson PK, Gekker G, Hu S, Chao CC (1995) Human astrocytes inhibit intracellular multiplication of Toxoplasma gondii by a nitric oxide-mediated mechanism. J Infect Dis 171:516–518

    PubMed  Article  CAS  Google Scholar 

  125. 125.

    Adams LB, Hibbs JB Jr, Taintor RR, Krahenbuhl JL (1990) Microbiostatic effect of murine-activated macrophages for Toxoplasma gondii. Role for synthesis of inorganic nitrogen oxides from l-arginine. J Immunol 144:2725–2729

    PubMed  CAS  Google Scholar 

  126. 126.

    Luder CG, Algner M, Lang C, Bleicher N, Gross U (2003) Reduced expression of the inducible nitric oxide synthase after infection with Toxoplasma gondii facilitates parasite replication in activated murine macrophages. Int J Parasitol 33:833–844

    PubMed  Article  CAS  Google Scholar 

  127. 127.

    Ibrahim HM, Bannai H, Xuan X, Nishikawa Y (2009) Toxoplasma gondii cyclophilin 18-mediated production of nitric oxide induces Bradyzoite conversion in a CCR5-dependent manner. Infect Immun 77:3686–3695

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  128. 128.

    Hayashi S, Chan CC, Gazzinelli R, Roberge FG (1996) Contribution of nitric oxide to the host parasite equilibrium in toxoplasmosis. J Immunol 156:1476–1481

    PubMed  CAS  Google Scholar 

  129. 129.

    Daubener W, Spors B, Hucke C, Adam R, Stins M, Kim KS, Schroten H (2001) Restriction of Toxoplasma gondii growth in human brain microvascular endothelial cells by activation of indoleamine 2,3-dioxygenase. Infect Immun 69:6527–6531

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  130. 130.

    Gupta SL, Carlin JM, Pyati P, Dai W, Pfefferkorn ER, Murphy MJ Jr (1994) Antiparasitic and antiproliferative effects of indoleamine 2,3-dioxygenase enzyme expression in human fibroblasts. Infect Immun 62:2277–2284

    PubMed  PubMed Central  CAS  Google Scholar 

  131. 131.

    Daubener W, Gutsche M, Nockemann S, MacKenzie C, Seghrouchni S, Hadding U (1996) Protamine enhances the activity of human recombinant interferon-gamma. J Interf Cytokine Res 16:531–536

    Article  CAS  Google Scholar 

  132. 132.

    Pfefferkorn ER (1984) Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. Proc Natl Acad Sci USA 81:908–912

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. 133.

    Murray HW, Szuro-Sudol A, Wellner D, Oca MJ, Granger AM, Libby DM, Rothermel CD, Rubin BY (1989) Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages. Infect Immun 57:845–849

    PubMed  PubMed Central  CAS  Google Scholar 

  134. 134.

    Divanovic S, Sawtell NM, Trompette A, Warning JI, Dias A, Cooper AM, Yap GS, Arditi M, Shimada K, Duhadaway JB, Prendergast GC, Basaraba RJ, Mellor AL, Munn DH, Aliberti J, Karp CL (2012) Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. J Infect Dis 205:152–161

    PubMed  Article  CAS  Google Scholar 

  135. 135.

    Sibley LD, Messina M, Niesman IR (1994) Stable DNA transformation in the obligate intracellular parasite Toxoplasma gondii by complementation of tryptophan auxotrophy. Proc Natl Acad Sci USA 91:5508–5512

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. 136.

    Schmitz JL, Carlin JM, Borden EC, Byrne GI (1989) Beta interferon inhibits Toxoplasma gondii growth in human monocyte-derived macrophages. Infect Immun 57:3254–3256

    PubMed  PubMed Central  CAS  Google Scholar 

  137. 137.

    Knubel CP, Martinez FF, Fretes RE, Diaz Lujan C, Theumer MG, Cervi L, Motran CC (2010) Indoleamine 2,3-dioxigenase (IDO) is critical for host resistance against Trypanosoma cruzi. FASEB J 24:2689–2701

    PubMed  Article  CAS  Google Scholar 

  138. 138.

    Tetsutani K, To H, Torii M, Hisaeda H, Himeno K (2007) Malaria parasite induces tryptophan-related immune suppression in mice. Parasitology 134:923–930

    PubMed  Article  CAS  Google Scholar 

  139. 139.

    Yap GS, Scharton-Kersten T, Charest H, Sher A (1998) Decreased resistance of TNF receptor p55- and p75-deficient mice to chronic toxoplasmosis despite normal activation of inducible nitric oxide synthase in vivo. J Immunol 160:1340–1345

    PubMed  CAS  Google Scholar 

  140. 140.

    Schluter D, Kwok LY, Lutjen S, Soltek S, Hoffmann S, Korner H, Deckert M (2003) Both lymphotoxin-alpha and TNF are crucial for control of Toxoplasma gondii in the central nervous system. J Immunol 170:6172–6182

    PubMed  Article  Google Scholar 

  141. 141.

    Weiss LM, Laplace D, Takvorian PM, Tanowitz HB, Cali A, Wittner M (1995) A cell culture system for study of the development of Toxoplasma gondii bradyzoites. J Eukaryot Microbiol 42:150–157

    PubMed  Article  CAS  Google Scholar 

  142. 142.

    Yap GS, Sher A (1999) Effector cells of both nonhemopoietic and hemopoietic origin are required for interferon (IFN)-gamma- and tumor necrosis factor (TNF)-alpha-dependent host resistance to the intracellular pathogen, Toxoplasma gondii. J Exp Med 189:1083–1092

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. 143.

    Gazzinelli RT, Hieny S, Wynn TA, Wolf S, Sher A (1993) Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci USA 90:6115–6119

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. 144.

    Streilein JW (1995) Ocular immune privilege in the immunosuppressive intraocular microenvironment. Ocular Immunol Inflamm 3:139–144

    Article  CAS  Google Scholar 

  145. 145.

    Wiendl H, Hohlfeld R, Kieseier BC (2005) Immunobiology of muscle: advances in understanding an immunological microenvironment. Trends Immunol 26:373–380

    PubMed  Article  CAS  Google Scholar 

  146. 146.

    Jones LA, Alexander J, Roberts CW (2006) Ocular toxoplasmosis: in the storm of the eye. Parasite Immunol 28:635–642

    PubMed  Article  CAS  Google Scholar 

  147. 147.

    Mahamed DA, Mills JH, Egan CE, Denkers EY, Bynoe MS (2012) CD73-generated adenosine facilitates Toxoplasma gondii differentiation to long-lived tissue cysts in the central nervous system. Proc Natl Acad Sci USA 109:16312–16317

    PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Israelski DM, Remington JS (1988) Toxoplasmic encephalitis in patients with AIDS. Infect Dis Clin N Am 2:429–445

    CAS  Google Scholar 

  149. 149.

    Gazzinelli R, Xu Y, Hieny S, Cheever A, Sher A (1992) Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. J Immunol 149:175–180

    PubMed  CAS  Google Scholar 

  150. 150.

    Suzuki Y, Remington JS (1989) A method for obtaining large numbers of trophozoites of avirulent strains of Toxoplasma gondii using an antibody to interferon-gamma. J Parasitol 75:174–176

    PubMed  Article  CAS  Google Scholar 

  151. 151.

    Suzuki Y, Joh K (1994) Effect of the strain of Toxoplasma gondii on the development of toxoplasmic encephalitis in mice treated with antibody to interferon-gamma. Parasitol Res 80:125–130

    PubMed  Article  CAS  Google Scholar 

  152. 152.

    Dunay IR, Chan WC, Haynes RK, Sibley LD (2009) Artemisone and artemiside control acute and reactivated toxoplasmosis in a murine model. Antimicrob Agents Chemother 53:4450–4456

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  153. 153.

    Jones TC, Bienz KA, Erb P (1986) In vitro cultivation of Toxoplasma gondii cysts in astrocytes in the presence of gamma interferon. Infect Immun 51:147–156

    PubMed  PubMed Central  CAS  Google Scholar 

  154. 154.

    Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34:7–11

    PubMed  Article  CAS  Google Scholar 

  155. 155.

    Holmes MJ, Augusto LDS, Zhang M, Wek RC, Sullivan WJ Jr (2017) Translational control in the latency of apicomplexan parasites. Trends Parasitol 33:947–960

    PubMed  Article  CAS  Google Scholar 

  156. 156.

    Sullivan WJ Jr, Narasimhan J, Bhatti MM, Wek RC (2004) Parasite-specific eIF2 (eukaryotic initiation factor-2) kinase required for stress-induced translation control. Biochem J 380:523–531

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  157. 157.

    Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307:935–939

    PubMed  Article  CAS  Google Scholar 

  158. 158.

    Tsaytler P, Harding HP, Ron D, Bertolotti A (2011) Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 332:91–94

    PubMed  Article  CAS  Google Scholar 

  159. 159.

    Konrad C, Queener SF, Wek RC, Sullivan WJ, Jr. (2013) Inhibitors of eIF2alpha dephosphorylation slow replication and stabilize latency in Toxoplasma gondii. Antimicrob Agents Chemother

  160. 160.

    Joyce BR, Tampaki Z, Kim K, Wek RC, Sullivan WJ Jr (2013) The unfolded protein response in the protozoan parasite Toxoplasma gondii features translational and transcriptional control. Eukaryot Cell 12:979–989

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  161. 161.

    Painter HJ, Campbell TL, Llinas M (2011) The apicomplexan AP2 family: integral factors regulating Plasmodium development. Mol Biochem Parasitol 176:1–7

    PubMed  Article  CAS  Google Scholar 

  162. 162.

    Cleary MD, Singh U, Blader IJ, Brewer JL, Boothroyd JC (2002) Toxoplasma gondii asexual development: identification of developmentally regulated genes and distinct patterns of gene expression. Eukaryot Cell 1:329–340

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  163. 163.

    Radke JR, Behnke MS, Mackey AJ, Radke JB, Roos DS, White MW (2005) The transcriptome of Toxoplasma gondii. BMC Biol 3:26

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  164. 164.

    Sullivan WJ Jr, Hakimi MA (2006) Histone mediated gene activation in Toxoplasma gondii. Mol Biochem Parasitol 148:109–116

    PubMed  Article  CAS  Google Scholar 

  165. 165.

    Meissner M, Soldati D (2005) The transcription machinery and the molecular toolbox to control gene expression in Toxoplasma gondii and other protozoan parasites. Microb Infect Inst Pasteur 7:1376–1384

    Article  CAS  Google Scholar 

  166. 166.

    Olguin-Lamas A, Madec E, Hovasse A, Werkmeister E, Callebaut I, Slomianny C, Delhaye S, Mouveaux T, Schaeffer-Reiss C, Van Dorsselaer A, Tomavo S (2011) A novel Toxoplasma gondii nuclear factor TgNF3 is a dynamic chromatin-associated component, modulator of nucleolar architecture and parasite virulence. PLoS Pathog 7:e1001328

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  167. 167.

    White MW, Radke JR, Radke JB (2014) Toxoplasma development—turn the switch on or off? Cell Microbiol 16:466–472

    PubMed  Article  CAS  Google Scholar 

  168. 168.

    Behnke MS, Wootton JC, Lehmann MM, Radke JB, Lucas O, Nawas J, Sibley LD, White MW (2010) Coordinated progression through two subtranscriptomes underlies the tachyzoite cycle of Toxoplasma gondii. PLoS One 5:e12354

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  169. 169.

    Radke JR, Striepen B, Guerini MN, Jerome ME, Roos DS, White MW (2001) Defining the cell cycle for the tachyzoite stage of Toxoplasma gondii. Mol Biochem Parasitol 115:165–175

    PubMed  Article  CAS  Google Scholar 

  170. 170.

    Croken MM, Ma Y, Markillie LM, Taylor RC, Orr G, Weiss LM, Kim K (2014) Distinct strains of Toxoplasma gondii feature divergent transcriptomes regardless of developmental stage. PLoS One 9:e111297

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  171. 171.

    Croken MM, Qiu W, White MW, Kim K (2014) Gene set enrichment analysis (GSEA) of Toxoplasma gondii expression datasets links cell cycle progression and the bradyzoite developmental program. BMC Genom 15:515

    Article  CAS  Google Scholar 

  172. 172.

    Saksouk N, Bhatti MM, Kieffer S, Smith AT, Musset K, Garin J, Sullivan WJ Jr, Cesbron-Delauw MF, Hakimi MA (2005) Histone-modifying complexes regulate gene expression pertinent to the differentiation of the protozoan parasite Toxoplasma gondii. Mol Cell Biol 25:10301–10314

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  173. 173.

    Naguleswaran A, Elias EV, McClintick J, Edenberg HJ, Sullivan WJ Jr (2010) Toxoplasma gondii lysine acetyltransferase GCN5-A functions in the cellular response to alkaline stress and expression of cyst genes. PLoS Pathog 6:e1001232

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  174. 174.

    Bougdour A, Maubon D, Baldacci P, Ortet P, Bastien O, Bouillon A, Barale JC, Pelloux H, Menard R, Hakimi MA (2009) Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites. J Exp Med 206:953–966

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  175. 175.

    Sautel CF, Cannella D, Bastien O, Kieffer S, Aldebert D, Garin J, Tardieux I, Belrhali H, Hakimi MA (2007) SET8-mediated methylations of histone H4 lysine 20 mark silent heterochromatic domains in apicomplexan genomes. Mol Cell Biol 27:5711–5724

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  176. 176.

    Dixon SE, Stilger KL, Elias EV, Naguleswaran A, Sullivan WJ Jr (2010) A decade of epigenetic research in Toxoplasma gondii. Mol Biochem Parasitol 173:1–9

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  177. 177.

    Bougdour A, Braun L, Cannella D, Hakimi MA (2010) Chromatin modifications: implications in the regulation of gene expression in Toxoplasma gondii. Cell Microbiol 12:413–423

    PubMed  Article  Google Scholar 

  178. 178.

    Gissot M, Kelly KA, Ajioka JW, Greally JM, Kim K (2007) Epigenomic modifications predict active promoters and gene structure in Toxoplasma gondii. PLoS Pathog 3:e77

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  179. 179.

    Sullivan WJ Jr, Smith AT, Joyce BR (2009) Understanding mechanisms and the role of differentiation in pathogenesis of Toxoplasma gondii: a review. Mem Inst Oswaldo Cruz 104:155–161

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  180. 180.

    Bhatti MM, Livingston M, Mullapudi N, Sullivan WJ Jr (2006) Pair of unusual GCN5 histone acetyltransferases and ADA2 homologues in the protozoan parasite Toxoplasma gondii. Eukaryot Cell 5:62–76

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  181. 181.

    Boyle JP, Rajasekar B, Saeij JP, Ajioka JW, Berriman M, Paulsen I, Roos DS, Sibley LD, White MW, Boothroyd JC (2006) 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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  182. 182.

    Jeffers V, Sullivan WJ Jr (2012) Lysine acetylation is widespread on proteins of diverse function and localization in the protozoan parasite Toxoplasma gondii. Eukaryot Cell 11:735–742

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  183. 183.

    Xue B, Jeffers V, Sullivan WJ, Uversky VN (2013) Protein intrinsic disorder in the acetylome of intracellular and extracellular Toxoplasma gondii. Mol BioSyst 9:645–657

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  184. 184.

    Sullivan WJ Jr, Monroy MA, Bohne W, Nallani KC, Chrivia J, Yaciuk P, Smith CK 2nd, Queener SF (2003) Molecular cloning and characterization of an SRCAP chromatin remodeling homologue in Toxoplasma gondii. Parasitol Res 90:1–8

    PubMed  Google Scholar 

  185. 185.

    Rooney PJ, Neal LM, Knoll LJ (2011) Involvement of a Toxoplasma gondii chromatin remodeling complex ortholog in developmental regulation. PLoS One 6:e19570

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  186. 186.

    Dalmasso MC, Onyango DO, Naguleswaran A, Sullivan WJ Jr, Angel SO (2009) Toxoplasma H2A variants reveal novel insights into nucleosome composition and functions for this histone family. J Mol Biol 392:33–47

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  187. 187.

    Nardelli SC, Che FY, Silmon de Monerri NC, Xiao H, Nieves E, Madrid-Aliste C, Angel SO, Sullivan WJ, Jr., Angeletti RH, Kim K, Weiss LM (2013) The histone code of Toxoplasma gondii comprises conserved and unique posttranslational modifications. mBio 4:e00922–e01013

  188. 188.

    Lekutis C, Ferguson DJ, Grigg ME, Camps M, Boothroyd JC (2001) Surface antigens of Toxoplasma gondii: variations on a theme. Int J Parasitol 31:1285–1292

    PubMed  Article  CAS  Google Scholar 

  189. 189.

    Lekutis C, Ferguson DJ, Boothroyd JC (2000) Toxoplasma gondii: identification of a developmentally regulated family of genes related to SAG2. Exp Parasitol 96:89–96

    PubMed  Article  CAS  Google Scholar 

  190. 190.

    Saeij JP, Arrizabalaga G, Boothroyd JC (2008) A cluster of four surface antigen genes specifically expressed in bradyzoites, SAG2CDXY, plays an important role in Toxoplasma gondii persistence. Infect Immun 76:2402–2410

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  191. 191.

    Schwarz JA, Fouts AE, Cummings CA, Ferguson DJ, Boothroyd JC (2005) A novel rhoptry protein in Toxoplasma gondii bradyzoites and merozoites. Mol Biochem Parasitol 144:159–166

    PubMed  Article  CAS  Google Scholar 

  192. 192.

    Lecordier L, Moleon-Borodowsky I, Dubremetz JF, Tourvieille B, Mercier C, Deslee D, Capron A, Cesbron-Delauw MF (1995) Characterization of a dense granule antigen of Toxoplasma gondii (GRA6) associated to the network of the parasitophorous vacuole. Mol Biochem Parasitol 70:85–94

    PubMed  Article  CAS  Google Scholar 

  193. 193.

    Patil V, Lescault PJ, Lirussi D, Thompson AB, Matrajt M (2012) Disruption of the expression of a non-coding RNA significantly impairs cellular differentiation in Toxoplasma gondii. Int J Mol Sci 14:611–624

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  194. 194.

    Milligan-Myhre KC, Rooney PJ, Knoll LJ (2011) Examination of a virulence mutant uncovers the ribosome biogenesis regulatory protein of Toxoplasma gondii. J Parasitol 97:1173–1177

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  195. 195.

    Joyce BR, Queener SF, Wek RC, Sullivan WJ Jr (2010) Phosphorylation of eukaryotic initiation factor-2{alpha} promotes the extracellular survival of obligate intracellular parasite Toxoplasma gondii. Proc Natl Acad Sci USA 107:17200–17205

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Michael White for his careful and critical review of our manuscript. Research in the laboratories of Drs. Sullivan and Kim is supported by Grants from the National Institutes of Health: AI116496 and AI124723 (WJS), R01AI087625 (KK), and AI092801 (to KK and WJS). This manuscript is dedicated to the memory of Dr. Zoi Tampaki who was a dedicated scientist, a valued colleague, and a beloved friend. We miss you every day.

Author information

Affiliations

  1. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Victoria Jeffers & William J. Sullivan Jr.

  2. Departments of Medicine, Microbiology and Immunology, and Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Zoi Tampaki & Kami Kim

  3. Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA

    Kami Kim

  4. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    William J. Sullivan Jr.

Authors
  1. Victoria Jeffers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zoi Tampaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kami Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William J. Sullivan Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Victoria Jeffers.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jeffers, V., Tampaki, Z., Kim, K. et al. A latent ability to persist: differentiation in Toxoplasma gondii. Cell. Mol. Life Sci. 75, 2355–2373 (2018). https://doi.org/10.1007/s00018-018-2808-x

Download citation

Keywords

  • Toxoplasma
  • Toxoplasmosis
  • Differentiation
  • Encystation
  • Tachyzoite
  • Bradyzoite
  • Latency
  • Gene regulation
  • Epigenetics
  • Immunity