Abstract
Infection with the obligate intracellular protozoan Toxoplasma gondii leads to lifelong persistence of the parasite in its mammalian hosts including humans. Apoptosis plays crucial roles in the interaction between the host and the parasite. This includes innate and adaptive defense mechanisms to restrict intracellular parasite replication as well as regulatory functions to modulate the host’s immune response. Not surprisingly, however, T. gondii also extensively modifies apoptosis of its own host cell or of uninfected bystander cells. After infection, apoptosis is triggered in T lymphocytes and other leukocytes, thereby leading to suppressed immune responses to the parasite. T cell apoptosis may be largely mediated by Fas engagement but also occurs independently of Fas under certain conditions. Depending on the magnitude of T cell apoptosis, it is either associated with unrestricted parasite replication and severe pathology or facilitates a stable parasite-host-interaction. However, T. gondii has also evolved strategies to inhibit host cell apoptosis. Apoptosis is blocked by indirect mechanisms in uninfected bystander cells, thereby modulating the inflammatory response to the parasite. In contrast, inhibition of apoptosis in infected host cells by direct interference with apoptosis-signaling cascades is thought to facilitate the intracellular development of T. gondii. Blockade of apoptosis by intracellular parasites may be achieved by different means including interference with the caspase cascade, increased expression of antiapoptotic molecules by infected host cells, and a decreased activity of the poly(ADP-ribose) polymerase. The intriguing dual activity of T. gondii to both promote and inhibit apoptosis requires a tight regulation to promote a stable parasite host-interaction and establishment of persistent toxoplasmosis.
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Keywords
- Toxoplasma Gondii
- Death Receptor Pathway
- Infected Host Cell
- Parasite Replication
- Growth Factor Withdrawal
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
References
Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326
Alano CC, Ying W, Swanson RA (2004) Poly(ADP-ribose) polymerase-1 mediated cell death in astrocytes requires NAD+ depletion and mitochondrial permeability transition. J Biol Chem Feb 11 [Epub ahead of print]
Ammassari A, Murri R, Cingolani A, De Luca A, Antinori A (1996) AIDS-associated cerebral toxoplasmosis: an update on diagnosis and treatment. In: U Gross (ed) Toxoplasma gondii. Curr Topics Microbiol Immunol 219, Springer, Berlin, pp 209–222
Barry M, McFadden G (1998) Apoptosis regulators from DNA viruses. Curr Opin Immunol 10:422–430
Beckers CJ, Dubremetz JF, Mercereau-Puijalon O, Joiner KA (1994) The Toxoplasma gondii rhoptry protein ROP2 is inserted into the parasitophorous vacuole membrane, surrounding the intracellular parasite, and is exposed to the host cell cytoplasm. J Cell Biol 127:947–961
Blader IJ, Manger ID, Boothroyd JC (2001) Microarray analysis reveals previously unknown changes in Toxoplasma gondii-infected human cells. J Biol Chem 276:24223–24231
Butcher BA, Kim L, Johnson PF, Denkers EY (2001) Toxoplasma gondii tachyzoites inhibit proinflammatory cytokine induction in infected macrophages by preventing nuclear translocation of the transcription factor NF-κB. J Immunol 167:2193–2201
Caamano J, Tato C, Cai G, Villegas EN, Speirs K, Craig L, Alexander J, Hunter CA (2000) Identification of a role for NF-κB2 in the regulation of apoptosis and in maintenance of T cell-mediated immunity to Toxoplasma gondii. J Immunol 165:5720–5728
Cesbron-Delauw M-F (1994) Dense-granule organelles of Toxoplasma gondii: their role in the host-parasite relationship. Parasitol Today 10:293–296
Channon JY, Miselis KA, Minns LA, Dutta C, Kasper LH (2002) Toxoplasma gondii induces granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor secretion by human fibroblasts: implications for neutrophil apoptosis. Infect Immun 70:6048–6057
Curiel TJ, Krug EC, Purner MB, Poignard P, Berens RL (1993) Cloned human CD4+ cytotoxic T lymphocytes specific for Toxoplasma gondii lyse tachyzoite-infected target cells. J Immunol 151:2024–2031
Denkers EY, Gazzinelli RT (1998) Regulation and function of T-cell mediated immunity during Toxoplasma gondii infection. Clin Microbiol Rev 11:569–588
Denkers EY, Yap G, Scharton-Kersten T, Charest H, Butcher BA, Caspar P, Heiny S, Sher A (1997) Perforin-mediated cytolysis plays a limited role in host resistance to Toxoplasma gondii. J Immunol 159:1903–1908
Deveraux QL, Roy N, Stennicke HR, van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 17:2215–2223
Gao L-Y, Kwaik YA (2000) The modulation of host cell apoptosis by intracellular bacterial pathogens. Trends Microbiol 8:306–313
Gavrilescu LC, Denkers EY (2001) IFN-γ overproduction and high level apoptosis are associated with high but not low virulence Toxoplasma gondii infection. J Immunol 167:902–909
Gavrilescu LC, Denkers EY (2003) Interleukin-12 p40-and Fas ligand-dependent apoptotic pathways involving STAT-1 phosphorylation are triggered during infection with a virulent strain of Toxoplasma gondii. Infect Immun 71:2577–2583
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
Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kühn R, Trinchieri G, Sher A (1996) In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ, and TNF-α. J Immunol 157:798–805
Goebel S, Gross U, Lüder CGK (2001) Inhibition of host cell apoptosis by Toxoplasma gondii is accompanied by reduced activation of the caspase cascade and alterations of poly(ADP-ribose) polymerase expression. J Cell Sci 114:3495–3505
Goebel S, Lüder CGK, Gross U (1999) Invasion by Toxoplasma gondii protects human-derived HL-60 cells from actinomycin D-induced apoptosis. Med Microbiol Immunol 187:221–226
Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312
Grigg ME, Bonnefoy S, Hehl AB, Suzuki Y, Boothroyd JC (2001) Success and virulence in Toxoplasma as the result of sexual recombination between two distinct ancestries. Science 294:161–165
Hakim FT, Gazzinelli RT, Denkers E, Hieny S, Shearer GM, Sher A (1991) CD8+ T cells from mice vaccinated against Toxoplasma gondii are cytotoxic for parasite-infected or antigen-pulsed host cells. J Immunol 147:2310–2316
Heussler VT, Küenzi P, Rottenberg S (2001) Inhibition of apoptosis by intracellular protozoan parasites. Int J Parasitol 31:1166–1176
Hisaeda H, Sakai T, Ishikawa H, Maekawa Y, Yasutomo K, Good RA, Himeno K (1997) Heat shock protein 65 induced by γδ T cells prevents apoptosis of macrophages and contributes to host defense in mice infected with Toxoplasma gondii. J Immunol 159:2375–2381
Hu MS, Schwartzman JD, Yeaman GR, Collins J, Seguin R, Khan IA, Kasper LH (1999) Fas-FasL interaction involved in pathogenesis of ocular toxoplasmosis in mice. Infect Immun 67:928–935
Jacobson MK, Jakobson EL (1999) Discovering new ADP-ribose polymer cycles: protecting the genome and more. TIBS 24:415–417
Joiner KA, Dubremetz JF (1993) Toxoplasma gondii: a protozoan for the nineties. Infect Immun 61:1169–1172
Kaufmann SH, Hengartner MO (2001) Programmed cell death: alive and well in the new millennium. Trends Cell Biol 11:526–534
Khan IA, Matsuura T, Kasper LH (1996) Activation-mediated CD4+ T cell unresponsiveness during acute Toxoplasma gondii infection in mice. Int Immunol 8:887–896
Kuwana T, Smith JS, Muzio M, Dixit V, Newmeyer DD, Kornbluth S (1998) Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c. J Biol Chem 273:16589–16594
Lee YH, Channon JY, Matsuura T, Schwartzman JD, Shin DW, Kasper LH (1999) Functional and quantitative analysis of splenic T cell responses following oral Toxoplasma gondii infection in mice. Exp Parasitol 91:212–221
Lieberman J (2003) The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nat Rev Immunol 3:361–370
Liesenfeld O, Kosek J, Remington JS, Suzuki Y (1996) Association of CD4+ T cell-dependent, interferon-γ-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii. J Exp Med 184:597–607
Liesenfeld O, Kosek JC, Suzuki Y (1997) Gamma interferon induces Fas-dependent apoptosis of Peyer’s patch T cells in mice following peroral infection with Toxoplasma gondii. Infect Immun 65:4682–4689
Lopes MF, da Veiga VF, Santos AR, Fonseca MEF, DosReis GA (1995) Activation-induced CD4+ T cell death by apoptosis in experimental Chagas’ disease. J Immunol 154:744–752
Lüder CGK, Gross U, Lopes MF (2001) Intracellular protozoan parasites and apoptosis: diverse strategies to modulate parasite-host interactions. Trends Parasitol 17:480–486
Luft BJ, Kansas G, Engleman EG, Remington JS (1984) Functional and quantitative alterations in T lymphocyte subpopulations in acute toxoplasmosis. J Infect Dis 150:761–767
McLeod R, Johnson J, Estes R, Mack D (1996) Immunogenetics in pathogenesis of and protection against toxoplasmosis. In:Gross U (ed) Toxoplasma gondii. Curr Topics Microbiol Immunol 219, Springer, Berlin, pp 95–112
Molestina RE, Payne TM, Coppens I, Sinai AP (2003) Activation of NF-κB by Toxoplasma gondii correlates with increased expression of antiapoptotic genes and localization of phosphorylated IκB to the parasitophorous vacuole membrane. J Cell Sci 116:4359–4371
Montoya JG, Lowe KE, Clayberger C, Moody D, Do D, Remington JS, Talib S, Subauste CS (1996) Human CD4+ and CD8+ T lymphocytes are both cytotoxic to Toxoplasma gondii-infected cells. Infect Immun 64:176–181
Mordue DG, Monroy F, La Regina M, Dinarello CA, Sibley LD (2001) Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines. J Immunol 167:4574–4584
Nash PB, Purner MB, Leon RP, Clarke P, Duke RC, Curiel TJ (1998) Toxoplasma gondii-infected cells are resistant to multiple inducers of apoptosis. J Immunol 160:1824–1830
Opferman JT, Korsmeyer SJ (2003) Apoptosis in the development and maintenance of the immune system. Nat Immunol 4:410–415
Orlofsky A, Somogyi RD, Weiss LM, Prystowsky MB (1999) The murine antiapoptotic protein A1 is induced in inflammatory macrophages and constitutively expressed in neutrophils. J Immunol 163:412–419
Orlofsky A, Weiss LM, Kawachi N, Prystowsky MB (2002) Deficiency in the antiapoptotic protein A1-a results in a diminished acute inflammatory response. J Immunol 168:1840–1846
Payne TM, Molestina RE, Sinai AP (2003) Inhibition of caspase activation and a requirement for NF-κB function in the Toxoplasma gondii-mediated blockade of host apoptosis. J Cell Sci 116:4345–4358
Petersen E, Pollak A, Reiter-Owona I (2001) Recent trends in research on congenital toxoplasmosis. Int J Parasitol 31:115–144
Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter ME (1999) Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem 274:22532–22538
Schwab JC, Beckers CJM, Joiner KA (1994) The parasitophorous vacuole membrane surrounding intracellular Toxoplasma gondii functions as a molecular sieve. Proc Natl Acad Sci USA 91:509–513
Shapira S, Speirs K, Gerstein A, Caamano J, Hunter CA (2002) Suppression of NF-κB activation by infection with Toxoplasma gondii. J Infect Dis 185[Suppl]:S66–S72
Sher A, Oswald IO, Hieny, S, Gazzinelli RT (1993) Toxoplasma gondii induces a T-independent IFN-γ response in NK cells which requires both adherent accessory cells and TNF-α. J Immunol 150:3982–3989
Sibley LD, Adams LB, Fukutomi Y, Krahenbuhl JL (1991) Tumor necrosis factor-α; triggers antitoxoplasmal activity of IFN-γ primed macrophages. J Immunol 147:2340–2345
Strickland GT and Sayles PC (1977) Depressed antibody responses to a thymus-dependent antigen in toxoplasmosis. Infect Immun 15:184–190
Suzuki Y, Orellana MA, Schreiber RD, Remington JS (1988) Interferon-γ: the major mediator of resistance against Toxoplasma gondii. Science 240:516–518
Suzuki Y, Remington JS (1988) Dual regulation of resistance against Toxoplasma gondii infection by Lyt-2+ and Lyt-1+, L3T4+ T cells in mice. J Immunol 140:3943–3946
Tanaka Y, Yoshihara K, Tohno Y, Kojima K, Kameoka M, Kamiya T (1995) Inhibition and down-regulation of poly(ADP-ribose) polymerase results in a marked resistance of HL-60 cells to various apoptosis-inducers. Cell Mol Biol 41:771–781
Tenter AM, Heckeroth AR, Weiss LM (2000) Toxoplasma gondii: from animals to humans. Int J Parasitol 30:1217–1258
Tibbetts MD, Zheng L, Lenardo MJ (2003) The death effector domain protein family: regulators of cellular homeostasis. Nature Immunol 4:404–409
Van Antwerp DJ, Martin SJ, Verma IM, Green DR (1998) Inhibition of TNF-induced apoptosis by NF-κB. Trends Cell Biol 8:107–111
Van Parijs L, Abbas AK (1996) Role of Fas-mediated cell death in the regulation of immune responses. Curr Opin Immunol 8:355–361
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin Jr AS (1998) NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281:1680–1683
Wei S, Marches F, Borvak J, Zou W, Channon J, White M, Radke J, Cesbron-Delauw M-F, Curiel TJ (2002) Toxoplasma gondii-infected human myeloid dendritic cells induce T-lymphocyte dysfunction and contact-dependent apoptosis. Infect Immun 70:1750–1760
Williams GT (1994) Programmed cell death: a fundamental protective response to pathogens. Trends Microbiol 2:463–464
Wing EJ, Boehmer SM, Christner LK (1983) Toxoplasma gondii: decreased resistance to intracellular bacteria in mice. Exp Parasitol 56:1–8
Yamashita K, Yui K, Ueda M, Yano A (1998) Cytotoxic T-lymphocyte-mediated lysis of Toxoplasma gondii-infected target cells does not lead to death of intracellular parasites. Infect Immun 66:4651–4655
Yano A, Norose K, Yamashita K, Aosai F, Sugane K, Segawa K, Hayashi S (1987) Immune response to Toxoplasma gondii-analysis of suppressor T cells in a patient with symptomatic acute toxoplasmosis. J Parasitol 73:954–961
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Lüder, C.G.K., Gross, U. (2005). Apoptosis and Its Modulation During Infection with Toxoplasma gondii: Molecular Mechanisms and Role in Pathogenesis. In: Griffin, D.E. (eds) Role of Apoptosis in Infection. Current Topics in Microbiology and Immunology, vol 289. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27320-4_10
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DOI: https://doi.org/10.1007/3-540-27320-4_10
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