Parasitology Research

, Volume 103, Issue 4, pp 829–838 | Cite as

P2X7 modulatory web in Trypanosoma cruzi infection

  • C. M. Cascabulho
  • R. F. S. Menna-Barreto
  • R. Coutinho-Silva
  • P. M. Persechini
  • A. Henriques-Pons
Original Paper


P2X7 is a member of the purinergic receptors family, with extracellular adenosine triphosphate (ATP) as the main agonist, promoting cations influx and membrane permeabilization that can lead to cell death. We previously proposed that extracellular ATP is involved in thymus atrophy induced by Trypanosoma cruzi infection through the induction of CD4+/CD8+ double-positive cell death and that P2X7 could be involved in this process. To further elucidate this possibility raised by in vitro assays, in this study, we used \({\text{P}}2{\text{X}}_7^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }} \) mice and observed no difference in thymus atrophy or parasitemia when compared to C57Bl/6. We then decided to investigate other aspects of purinergic receptor interplay that could be better evidenced by the infection and observed that (1) thymocytes from infected and noninfected C57Bl/6 mice express P2X4 and P2X7 receptors (Western blotting), but ATP-induced membrane permeabilization only occurs in thymocytes from infected mice; (2) peritoneal macrophages from noninfected C57Bl/6 mice (\({\text{P}}2{\text{X}}_4^ + \) and \({\text{P}}2{\text{X}}_7^ + \)) are permeabilized by ATP. Although macrophages from infected C57Bl/6 mice are \({\text{P}}2{\text{X}}_7^ - \) but \({\text{P}}2{\text{X}}_4^ + \), they are resistant to ATP, either through permeabilization or Ca++ influx (fluorimetry); (3) using noninfected \({\text{P}}2{\text{X}}_7^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }} \) mice, C57Bl/6 infected mice, and different agonistic stimuli, we observed interesting cross-talks among P2X and P2Y receptors (flow cytometry).


  1. Adriouch S, Dox C, Welge V, Seman M, Koch-Nolte F, Haag F (2002) Cutting edge: a natural P451L mutation in the cytoplasmic domain impairs the function of the mouse P2X7 receptor. J Immunol 169:4108–4112PubMedGoogle Scholar
  2. Araujo-Jorge TC, Sampaio EP, De Souza W, Meirelles N (1989) Trypanosoma cruzi: the effect of variations in experimental conditions on the levels of macrophage infection in vitro. Parasitol Res 75:257–263PubMedCrossRefGoogle Scholar
  3. Cabrini G, Falzoni S, Forchap SL, Pellegatti P, Balboni A, Agostini P, Cuneo A, Castoldi G, Baricordi OR, Di Virgilio F (2005) A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes. J Immunol 175:82–89PubMedGoogle Scholar
  4. Coddou C, Morales B, Huidobro-Toro JP (2003) Neuromodulator role of zinc and copper during prolonged ATP applications to P2X4 purinoceptors. Eur J Pharmacol 472:49–56PubMedCrossRefGoogle Scholar
  5. Cotta-de-Almeida V, Bertho AL, Villa-Verde DM, Savino W (1997) Phenotypic and functional alterations of thymic nurse cells following acute Trypanosoma cruzi infection. Clin Immunol Immunopathol 82:125–132PubMedCrossRefGoogle Scholar
  6. Cotta-de-Almeida V, Bonomo A, Mendes-da-Cruz DA, Riederer I, De Meis J, Lima-Quaresma KR, Vieira-de-Abreu A, Villa-Verde DM, Savino W (2003) Trypanosoma cruzi infection modulates intrathymic contents of extracellular matrix ligands and receptors and alters thymocyte migration. Eur J Immunol 33:2439–2448PubMedCrossRefGoogle Scholar
  7. Coura JR (2007) Chagas disease: what is known and what is needed-a background article. Mem Inst Oswaldo Cruz 102(Suppl 1):113–122PubMedGoogle Scholar
  8. Coutinho-Silva R, Persechini PM (1997) P2Z purinoceptor-associated pores induced by extracellular ATP in macrophages and J774 cells. Am J Physiol 273:C1793–C1800PubMedGoogle Scholar
  9. Coutinho-Silva R, Perfettini JL, Persechini PM, Dautry-Varsat A, Ojcius DM (2001) Modulation of P2Z/P2X(7) receptor activity in macrophages infected with Chlamydia psittaci. Am J Physiol 280:C81–C89Google Scholar
  10. Dubyak GR (2007) Go it alone no more-P2X7 joins the society of heteromeric ATP-gated receptor channels. Mol Pharmacol 72:1402–1405PubMedCrossRefGoogle Scholar
  11. Eschke D, Wust M, Hauschildt S, Nieber K (2002) Pharmacological characterization of the P2X(7) receptor on human macrophages using the patch-clamp technique. Naunyn-Schmiedeberg’s Arch Pharmacol 365:168–171CrossRefGoogle Scholar
  12. Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, Panther E, Di Virgilio F (2006) The P2X7 receptor: a key player in IL-1 processing and release. J Immunol 176:3877–3883PubMedGoogle Scholar
  13. Freire-de-Lima CG, Nascimento DO, Soares MB, Bozza PT, Castro-Faria-Neto HC, de Mello FG, DosReis GA, Lopes MF (2000) Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature 403:199–203PubMedCrossRefGoogle Scholar
  14. Gu B, Bendall LJ, Wiley JS (1998) Adenosine triphosphate-induced shedding of CD23 and L-selectin (CD62L) from lymphocytes is mediated by the same receptor but different metalloproteases. Blood 92:946–951PubMedGoogle Scholar
  15. Guo C, Masin M, Qureshi OS, Murrell-Lagnado RD (2007) Evidence for functional P2X4/P2X7 heteromeric receptors. Mol Pharmacol 72:1447–1456PubMedCrossRefGoogle Scholar
  16. Hardy AR, Jones ML, Mundell SJ, Poole AW (2004) Reciprocal cross-talk between P2Y1 and P2Y12 receptors at the level of calcium signaling in human platelets. Blood 104:1745–1752PubMedCrossRefGoogle Scholar
  17. Higuchi ML, Benvenuti LA, Martins Reis M, Metzger M (2003) Pathophysiology of the heart in Chagas’ disease: current status and new developments. Cardiovasc Res 60(1):96–107CrossRefGoogle Scholar
  18. Humphreys BD, Dubyak GR (1998) Modulation of P2X7 nucleotide receptor expression by pro- and anti-inflammatory stimuli in THP-1 monocytes. J Leukoc Biol 64:265–273PubMedGoogle Scholar
  19. Leite-de-Moraes MC, Hontebeyrie-Joskowicz M, Dardenne M, Savino W (1992) Modulation of thymocyte subsets during acute and chronic phases of experimental Trypanosoma cruzi infection. Immunology 77:95–98PubMedGoogle Scholar
  20. Lopes MF, Nunes MP, Henriques-Pons A, Giese N, Morse HC, Davidson WF, Araujo-Jorge TC, DosReis GA (1999) Increased susceptibility of Fas ligand-deficient gld mice to Trypanosoma cruzi infection due to a Th2-biased host immune response. Eur J Immunol 29:81–89PubMedCrossRefGoogle Scholar
  21. Mantuano-Barradas M, Henriques-Pons A, Araujo-Jorge TC, Di Virgilio F, Coutinho-Silva R, Persechini PM (2003) Extracellular ATP induces cell death in CD4+/CD8+ double-positive thymocytes in mice infected with Trypanosoma cruzi. Microbes Infect 5:1363–1371PubMedCrossRefGoogle Scholar
  22. Minoprio P, Itohara S, Heusser C, Tonegawa S, Coutinho A (1989) Immunobiology of murine Trypanosoma cruzi infection: the predominance of parasite-nonspecific responses and the activation of TCRI T cells. Immunol Rev 112:183–207PubMedCrossRefGoogle Scholar
  23. Moncayo A (2003) Chagas disease: current epidemiological trends after the interruption of vectorial and transfusional transmission in the Southern Cone countries. Mem Inst Oswaldo Cruz 98(5):577–591PubMedCrossRefGoogle Scholar
  24. Mucci J, Hidalgo A, Mocetti E, Argibay PF, Leguizamon MS, Campetella O (2002) Thymocyte depletion in Trypanosoma cruzi infection is mediated by trans-sialidase-induced apoptosis on nurse cells complex. Proc Natl Acad Sci USA 99:3896–3901PubMedCrossRefGoogle Scholar
  25. Mucci J, Mocetti E, Leguizamon MS, Campetella O (2005) A sexual dimorphism in intrathymic sialylation survey is revealed by the trans-sialidase from Trypanosoma cruzi. J Immunol 174:4545–4550PubMedGoogle Scholar
  26. Pelegrin P, Surprenant A (2006) Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 25:5071–5082PubMedCrossRefGoogle Scholar
  27. Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492PubMedGoogle Scholar
  28. Shemon AN, Sluyter R, Fernando SL, Clarke AL, Dao-Ung LP, Skarratt KK, Saunders BM, Tan KS, Gu BJ, Fuller SJ, Britton WJ, Petrou S, Wiley JS (2006) A Thr357 to Ser polymorphism in homozygous and compound heterozygous subjects causes absent or reduced P2X7 function and impairs ATP-induced mycobacterial killing by macrophages. J Biol Chem 281:2079–2086PubMedCrossRefGoogle Scholar
  29. Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, Griffiths RJ, Gabel CA (2001) Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem 276:125–132PubMedCrossRefGoogle Scholar
  30. Sugiyama T, Kawamura H, Yamanishi S, Kobayashi M, Katsumura K, Puro DG (2005) Regulation of P2X7-induced pore formation and cell death in pericyte-containing retinal microvessels. Am J Physiol 288:C568–576CrossRefGoogle Scholar
  31. Surprenant A, Schneider DA, Wilson HL, Galligan JJ, North RA (2000) Functional properties of heteromeric P2X(1/5) receptors expressed in HEK cells and excitatory junction potentials in guinea-pig submucosal arterioles. J Auton Nerv Syst 81:249–263PubMedCrossRefGoogle Scholar
  32. Tsukimoto M, Maehata M, Harada H, Ikari A, Takagi K, Degawa M (2006) P2X7 receptor-dependent cell death is modulated during murine T cell maturation and mediated by dual signaling pathways. J Immunol 177:2842–2850PubMedGoogle Scholar
  33. Virginio C, MacKenzie A, Rassendren FA, North RA, Surprenant A (1999) Pore dilation of neuronal P2X receptor channels. Nat Neurosci 2:315–321PubMedCrossRefGoogle Scholar
  34. Volonte C, Amadio S, D’Ambrosi N, Colpi M, Burnstock G (2006) P2 receptor web: complexity and fine-tuning. Pharmacol Ther 112:264–280PubMedCrossRefGoogle Scholar
  35. WHO (2004) Online newsletter: TDRNews. Available at: Access: May 2007

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • C. M. Cascabulho
    • 1
  • R. F. S. Menna-Barreto
    • 1
  • R. Coutinho-Silva
    • 2
  • P. M. Persechini
    • 2
  • A. Henriques-Pons
    • 1
  1. 1.Laboratório de Biologia Celular, Fundação Oswaldo CruzInstituto Oswaldo Cruz, FIOCRUZRio de JaneiroBrazil
  2. 2.Laboratório de Imunobiofísica, Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil

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