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Toxoplasma gondii: determinants of tachyzoite to bradyzoite conversion

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Abstract

Apicomplexa are primarily obligate intracellular protozoa that have evolved complex developmental stages important for pathogenesis and transmission. Toxoplasma gondii, responsible for the disease toxoplasmosis, has the broadest host range of the Apicomplexa as it infects virtually any warm-blooded vertebrate host. Key to T. gondii’s pathogenesis is its ability to differentiate from a rapidly replicating tachyzoite stage during acute infection to a relatively non-immunogenic, dormant bradyzoite stage contained in tissue cysts. These bradyzoite cysts can reconvert back to tachyzoites years later causing serious pathology and death if a person becomes immune-compromised. Like the sexual stage sporozoites, bradyzoites are also orally infectious and a major contributor to transmission. Because of the critical role of stage conversion to pathogenesis and transmission, a major research focus is aimed at identifying molecular mediators and pathways that regulate differentiation. Tachyzoite to bradyzoite development can occur spontaneously in vitro and be induced in response to exogenous stress including but not limited to host immunity. The purpose of this review is to explore the potential contributors to stage differentiation in infection and how a determination is made by the parasite to differentiate from tachyzoites to bradyzoites.

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References

  • Appelberg R (2006) Macrophage nutriprive antimicrobial mechanisms. J Leukoc Biol 79:1117–1128

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Bozdech Z, Llinas M, Pulliam BL, Wong ED, Zhu J, DeRisi JL (2003) The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLoS Biol 1:E5

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • De Groote MA, Fang FC (1995) NO inhibitions: antimicrobial properties of nitric oxide. Clin Infect Dis 21(Suppl 2):S162–S165

    PubMed  Google Scholar 

  • Donald RG, Liberator PA (2002) Molecular characterization of a coccidian parasite cGMP dependent protein kinase. Mol Biochem Parasitol 120:165–175

    Article  CAS  PubMed  Google Scholar 

  • Donald RG, Allocco J, Singh SB, Nare B, Salowe SP, Wiltsie J, Liberator PA (2002) Toxoplasma gondii cyclic GMP-dependent kinase: chemotherapeutic targeting of an essential parasite protein kinase. Eukaryot Cell 1:317–328

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Dubey JP, Frenkel JK (1976) Feline toxoplasmosis from acutely infected mice and the development of Toxoplasma cysts. J Protozool 23:537–546

    CAS  PubMed  Google Scholar 

  • Dubey JP, Lindsay DS, Speer CA (1998) Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts. Clin Microbiol Rev 11:267–299

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Eaton MS, Weiss LM, Kim K (2006) Cyclic nucleotide kinases and tachyzoite–bradyzoite transition in Toxoplasma gondii. Int J Parasitol 36:107–114

    Article  CAS  PubMed  Google Scholar 

  • Echeverria PC, Matrajt M, Harb OS, Zappia MP, Costas MA, Roos DS, Dubremetz JF, Angel S (2005) Toxoplasma gondii Hsp90 is a potential drug target whose expression and subcellular localization are developmentally regulated. J Mol Biol 350:723–734

    Article  CAS  PubMed  Google Scholar 

  • Fang FC (2004) Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol 2:820–832

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Ferreira-da-Silva MF, Rodrigues RM, Andrade EF, Carvalho L, Gross U, Luder CG, Barbosa HS (2009a) Spontaneous stage differentiation of mouse-virulent Toxoplasma gondii RH parasites in skeletal muscle cells: an ultrastructural evaluation. Mem Inst Oswaldo Cruz 104:196–200

    Article  Google Scholar 

  • Ferreira-da-Silva MF, Takacs AC, Barbosa HS, Gross U, Luder CG (2009b) Primary skeletal muscle cells trigger spontaneous Toxoplasma gondii tachyzoite-to-bradyzoite conversion at higher rates than fibroblasts. Int J Med Microbiol 299:381–388

    Article  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Gubbels MJ, White M, Szatanek T (2008) The cell cycle and Toxoplasma gondii cell division: tightly knit or loosely stitched? Int J Parasitol 38:1343–1358

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Hayashi S, Chan CC, Gazzinelli RT, Pham NT, Cheung MK, Roberge FG (1996) Protective role of nitric oxide in ocular toxoplasmosis. Br J Ophthalmol 80:644–648

    Article  CAS  PubMed  Google Scholar 

  • Heikkila JJ (1993a) Heat shock gene expression and development. I. An overview of fungal, plant, and poikilothermic animal developmental systems. Dev Genet 14:1–5

    Article  CAS  PubMed  Google Scholar 

  • Heikkila JJ (1993b) Heat shock gene expression and development. II. An overview of mammalian and avian developmental systems. Dev Genet 14:87–91

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Jerome ME, Radke JR, Bohne W, Roos DS, White MW (1998) Toxoplasma gondii bradyzoites form spontaneously during sporozoite-initiated development. Infect Immun 66:4838–4844

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Kirkman LA, Weiss LM, Kim K (2001) Cyclic nucleotide signaling in Toxoplasma gondii bradyzoite differentiation. Infect Immun 69:148–153

    Article  CAS  PubMed  Google Scholar 

  • Luder CG, Giraldo-Velasquez M, Sendtner M, Gross U (1999) Toxoplasma gondii in primary rat CNS cells: differential contribution of neurons, astrocytes, and microglial cells for the intracerebral development and stage differentiation. Exp Parasitol 93:23–32

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Lyons RE, Johnson AM (1995) Heat shock proteins of Toxoplasma gondii. Parasite Immunol 17:353–359

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Nare B, Allocco JJ, Liberator PA, Donald RG (2002) Evaluation of a cyclic GMP-dependent protein kinase inhibitor in treatment of murine toxoplasmosis: gamma interferon is required for efficacy. Antimicrob Agents Chemother 46:300–307

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Roberts F, Roberts CW, Ferguson DJ, McLeod R (2000) Inhibition of nitric oxide production exacerbates chronic ocular toxoplasmosis. Parasite Immunol 22:1–5

    Article  CAS  PubMed  Google Scholar 

  • Scharton-Kersten TM, Yap G, Magram J, Sher A (1997) Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii. J Exp Med 185:1261–1273

    Article  CAS  PubMed  Google Scholar 

  • Schlüter D, Deckert-Schlüter M, Lorenz E, Meyer T, Röllinghoff M, Bogdan C (1999) Inhibition of inducible nitric oxide synthase exacerbates chronic cerebral toxoplasmosis in Toxoplasma gondii-susceptible C57BL/6 mice but does not reactivate the latent disease in T. gondii-resistant BALB/c mice. J Immunol 162:3512–3518

    PubMed  Google Scholar 

  • Sibley LD, Ajioka JW (2008) Population structure of Toxoplasma gondii: clonal expansion driven by infrequent recombination and selective sweeps. Annu Rev Microbiol 62:329–351

    Article  CAS  PubMed  Google Scholar 

  • Sibley LD, Khan A, Ajioka JW, Rosenthal BM (2009) Genetic diversity of Toxoplasma gondii in animals and humans. Philos Trans R Soc Lond B Biol Sci 364:2749–2761

    Article  PubMed  Google Scholar 

  • Silva NM, Gazzinelli RT, Silva DA, Ferro EA, Kasper LH, Mineo JR (1998) Expression of Toxoplasma gondii-specific heat shock protein 70 during in vivo conversion of bradyzoites to tachyzoites. Infect Immun 66:3959–3963

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Soete M, Fortier B, Camus D, Dubremetz JF (1993) Toxoplasma gondii: kinetics of bradyzoite–tachyzoite interconversion in vitro. Exp Parasitol 76:259–264

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Suzuki Y, Conley FK, Remington JS (1989) Importance of endogenous IFN-gamma for prevention of toxoplasmic encephalitis in mice. J Immunol 143:2045–2050

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank our colleagues in the T. gondii field for their pioneering work and insights into T. gondii stage conversion as well as for fruitful discussions at meetings. We also thank the National Institute of Health for their financial support (AI072028 to DGM).

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  1. Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, 10595, USA

    Sini Skariah, Matthew Karmen McIntyre & Dana G. Mordue

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  1. Sini Skariah
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  2. Matthew Karmen McIntyre
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  3. Dana G. Mordue
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Correspondence to Dana G. Mordue.

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Skariah, S., McIntyre, M.K. & Mordue, D.G. Toxoplasma gondii: determinants of tachyzoite to bradyzoite conversion. Parasitol Res 107, 253–260 (2010). https://doi.org/10.1007/s00436-010-1899-6

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