Skip to main content

Advertisement

SpringerLink
Log in

Toxoplasma gondii Dense Granule Antigen 1 stimulates apoptosis of monocytes through autocrine TGF-β signaling

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Monocyte/macrophages represent the first line of defense against protozoan parasites. Different mechanisms of monocyte suppression by Toxoplasma gondii that sustain parasite invasion and persistence have been described, including apoptosis. In the present study, we investigated the effect of microbial excretory–secretory polypeptides, namely the microneme protein MIC3 and the dense granule antigen GRA1, on apoptosis of monocytes from patients with congenital toxoplasmosis and healthy individuals. We found that GRA1 but not MIC3 could induce apoptosis of monocytes, observing the effect in samples from both Toxoplasma-infected and uninfected individuals, thus ruling out involvement of mechanisms of apoptosis linked to adaptive immunity or a cellular context related to infection. Selective inhibition of TGF-β type I receptors reversed GRA1-induced apoptosis, indicating that this apoptosis involved canonical TGF-β signaling. By using TGF-β-neutralizing antibodies, we showed that monocyte apoptosis required endogenous TGF-β and that GRA1 stimulation activated TGF-β transcription and expression in monocytes but not lymphocytes, suggesting involvement of an autocrine TGF-β-mediated mechanism in GRA1-induced apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  2. Petersen E (2007) Toxoplasmosis. Semin Fetal Neonatal Med 12:214–223 (review)

  3. Subauste CS, Remington JS (1993) Immunity to Toxoplasma gondii. Curr Opin Immunol 5:532–537

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  5. Pollard AM, Knoll LJ, Mordue DG (2009) The role of specific Toxoplasma gondii molecules in manipulation of innate immunity. Trends Parasitol 25:491–494

    Article  PubMed  CAS  Google Scholar 

  6. Hunter CA, Bermudez L, Beernink H, Waegell W, Remington JS (1995) Transforming growth factor-beta inhibits interleukin-12-induced production of interferon-gamma by natural killer cells: a role for transforming growth factor-beta in the regulation of T cell-independent resistance to Toxoplasma gondii. Eur J Immunol 25:994–1000

    Article  PubMed  CAS  Google Scholar 

  7. Ellis Neyer L, Grunig G, Fort M, Remington JS, Rennick D, Hunter CA (1997) Role of interleukin-10 in regulation of T-cell-dependent and T-cell-independent mechanisms of resistance to Toxoplasma gondii. Infect Immun 65:1675–1682

    Google Scholar 

  8. Langermans JAM, Nibbering PH, van Vuren MEB, van der Hulst M, van Furth R (2001) Transforming growth factor suppresses interferon-induced Toxoplasma static activity in murine macrophages by inhibition of tumour necrosis factor production. Parasite Immunol 23:169–175

    Article  PubMed  CAS  Google Scholar 

  9. Aliberti J, Hieny S, Reis e Sousa C, Serhan CN, Sher A (2001) Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nat Immunol 3:76–82

    Article  PubMed  Google Scholar 

  10. 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

    Article  PubMed  CAS  Google Scholar 

  11. 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

    PubMed  CAS  Google Scholar 

  12. Nishikawa Y, Kawase O, Vielemeyer O, Suzuki H, Joiner KA, Xuan X, Nagasawa H (2007) Toxoplasma gondii infection induces apoptosis in noninfected macrophages: role of nitric oxide and other soluble factors. Parasite Immunol 29:375–385

    Article  PubMed  CAS  Google Scholar 

  13. Beghetto E, Spadoni A, Buffolano W, Del Pezzo M, Minenkova O, Pavoni E, Pucci A, Cortese R, Felici F, Gargano N (2003) Molecular dissection of the human B-cell response against Toxoplasma gondii infection by lambda display of cDNA libraries. Int J Parasitol 33:163–173

    Article  PubMed  CAS  Google Scholar 

  14. Letterio JJ, Lehrnbecher T, Pollack G, Walsh TJ, Chanock SJ (2001) Invasive candidiasis stimulates hepatocyte and monocyte production of active transforming growth factor beta. Infect Immun 69:5115–5120

    Article  PubMed  CAS  Google Scholar 

  15. Sly LM, Rauh MJ, Kalesnikoff J, Song CH, Krystal G (2004) LPS induced upregulation of SHIP is essential for endotoxin tolerance. Immunity 21:227–239

    Article  PubMed  CAS  Google Scholar 

  16. Bermudez LE, Covaro G, Remington J (1993) Infection of murine macrophages with Toxoplasma gondii is associated with release of transforming growth factor beta and downregulation of expression of tumor necrosis factor receptors. Infect Immun 61:4126–4130

    PubMed  CAS  Google Scholar 

  17. Giordano A, Romano S, Mallardo M, D’Angelillo A, Calì G, Corcione N, Ferraro P, Romano MF (2008) FK506 can activate TGF-{beta} signaling in vascular smooth muscle cells and promote proliferation. Cardiovasc Res 79:519–526

    Article  PubMed  CAS  Google Scholar 

  18. Birchenall-Roberts MC, Ruscetti FW, Kasper J, Lee HD, Friedman R, Geiser A, Sporn MB, Roberts AB, Kim SJ (1990) Transcriptional regulation of the transforming growth factor beta 1 promoter by v-src gene products is mediated through the AP-1 complex. Mol Cell Biol 10:4978–4983

    PubMed  CAS  Google Scholar 

  19. Denkers EY (2003) From cells to signaling cascades: manipulation of innate immunity by Toxoplasma gondii. FEMS Immunol Med Microbiol 39:193–203

    Article  PubMed  CAS  Google Scholar 

  20. Chen M, Wang Y-H, Wang Y, Huang L, Sandoval H, Liu Y-L, Wang J (2006) Dendritic cell apoptosis in the maintenance of immune tolerance. Science 311:1160–1164

    Article  PubMed  CAS  Google Scholar 

  21. Serbina NV, Jia T, Hohl TM, Pamer EG (2008) Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 26:421–452

    Article  PubMed  CAS  Google Scholar 

  22. Saeij JP, Coller S, Boyle JP, Jerome ME, White MW, Boothroyd JC (2007) Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature 445:324–327

    Article  PubMed  CAS  Google Scholar 

  23. Yamamoto M, Standley DM, Takashima S, Saiga H, Okuyama M, Kayama H, Kubo E, Ito H, Takaura M, Matsuda T, Soldati-Favre D, Takeda K (2009) 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

    Article  PubMed  CAS  Google Scholar 

  24. Mercier C, Adjogble KD, Däubener W, Delauw MF (2005) Dense granules: are they key organelles to help understand the parasitophorous vacuole of all apicomplexa parasites? Int J Parasitol 35:829–849

    Article  PubMed  Google Scholar 

  25. Nam HW (2009) GRA proteins of Toxoplasma gondii: maintenance of host–parasite interactions across the parasitophorous vacuolar membrane. Korean J Parasitol 47(Suppl):S29–S37

    Article  PubMed  CAS  Google Scholar 

  26. Mercier C, Dubremetz JF, Rauscher B, Lecoedier L, Sibley LD, Cesbron-DeLauw MF (2002) Biogenesis of nanotubular network in Toxoplasma parasitophorous vacuole induced by parasite proteins. Mol Biol Cell 13:2397–2409

    Article  PubMed  CAS  Google Scholar 

  27. Beghetto E, Pucci A, Minenkova O, Spadoni A, Bruno L, Buffolano W, Soldati D, Felici F, Gargano N (2001) Identification of a human immonodominant B-cell epitope within GRA1 antigen of Toxoplasma gondii. Int J Parasitol 31:1659–1668

    Article  PubMed  CAS  Google Scholar 

  28. Guglietta S, Beghetto E, Spadoni A, Buffolano W, Del Porto P, Gargano N (2007) Age-dependent impairment of functional helper T cell responses to immunodominant epitopes of Toxoplasma gondii antigens in congenitally infected individuals. Microbes Infect 9:127–133

    Article  PubMed  CAS  Google Scholar 

  29. Jang CW, Chen CH, Chen CC, Chen JY, Su YH, Chen RH (2002) TGF-b induces apoptosis through Smad-mediated expression of DAP-kinase. Nat Cell Biol 4:51–58

    Article  PubMed  CAS  Google Scholar 

  30. Perlman R, Schiemann WP, Brooks MW, Lodish HF, Weinberg RA (2001) TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol 3:708–714

    Article  PubMed  CAS  Google Scholar 

  31. Massague J, Blain SW (2000) TGF-b signaling in growth control, cancer, and heritable disorders. Cell 103:295–309

    Article  PubMed  CAS  Google Scholar 

  32. Pinon JD, Labi V, Egle A, Villunger A (2008) Bim and Bmf in tissue homeostasis and malignant disease. Oncogene 27:S41–S52

    Article  PubMed  CAS  Google Scholar 

  33. Gaddi PJ, Yap GS (2007) Cytokine regulation of immunopathology in toxoplasmosis. Immunol Cell Biol 85:155–159

    Article  PubMed  CAS  Google Scholar 

  34. Kasper L, Courret N, Darche S, Luangsay S, Mennechet LM, Rachinel N, Ronet C, Buzoni-Gatel D (2004) Toxoplasma gondii and mucosal immunity. Int J Parasitol 34:401–409

    Article  PubMed  CAS  Google Scholar 

  35. Dunay IR, DaMatta RA, Fux B, Presti R, Greco S, Colonna M, Sibley LD (2008) Gr1+ inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity 29:306–317

    Article  PubMed  CAS  Google Scholar 

  36. Robben PM, LaRegina M, Kuziel WA, Sibley LD (2005) Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis. J Exp Med 201:1761–1769

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by funds from the Italian Association for Cancer Research (AIRC) and the Italian Ministry of University and Research (MIUR).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Medical Biotechnology, University of Naples “Federico II”, Via S. Pansini 5, 80131, Naples, Italy

    Anna D’Angelillo, Elvira De Luna, Simona Romano, Rita Bisogni & Maria Fiammetta Romano

  2. Department of Pediatrics—Perinatal Infection Unit, University of Naples “Federico II”, Naples, Italy

    Wilma Buffolano

  3. Kenton Laboratories, Kenton S.r.l., Rome, Italy

    Nicola Gargano

  4. Department of Cellular and Developmental Biology, University of Rome “La Sapienza”, Rome, Italy

    Paola Del Porto

  5. CEINGE Biotecnologie Avanzate, Naples, Italy

    Luigi Del Vecchio

  6. Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark

    Eskild Petersen

Authors
  1. Anna D’Angelillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elvira De Luna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simona Romano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rita Bisogni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wilma Buffolano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nicola Gargano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paola Del Porto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luigi Del Vecchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eskild Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maria Fiammetta Romano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Fiammetta Romano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

D’Angelillo, A., De Luna, E., Romano, S. et al. Toxoplasma gondii Dense Granule Antigen 1 stimulates apoptosis of monocytes through autocrine TGF-β signaling. Apoptosis 16, 551–562 (2011). https://doi.org/10.1007/s10495-011-0586-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-011-0586-0

Keywords

Search

Navigation