Regulation of Innate Immunity During Trypanosoma cruzi Infection

  • Fredy Roberto Salazar Gutierrez


Chagas Heart disease is caused by the infection with T. cruzi. The mechanisms of disease progression remain largely unknown although it has been reported that parasite persistence as well as the intensity of the inflammatory immune response are determinants for the clinical manifestations of the disease.

Through a long co-evolutionary history, both the human immune system and the pathogen have acquired diverse mechanisms to interact, guaranteeing their mutual survival. Even though inflammation is indispensable for host defense and tissue repair, when deregulated or disproportionate, it can contribute to continuous tissue injury, organ dysfunction, and disease. Thus, the immune system has acquired a great complexity in order to maintain the host’s integrity while it is able to arrest the proliferation of pathogens as soon as detected.

This chapter aims to review the regulatory mechanisms involved in the control of the effectors mechanisms of the innate immunity during experimental T. cruzi infection and Chagas disease. It provides a comprehensive revision of the immunologic mechanisms triggered by the interaction of the parasite and the host cells during acute phase of the infection, as well as the possible implications for the design of therapeutic or diagnostic approaches.


Nitric Oxide Nitric Oxide Innate Immunity Migration Inhibitor Factor Trypanosoma Cruzi 
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.


  1. Akira, S., S. Uematsu, et al. (2006). “Pathogen recognition and innate immunity.” Cell 124(4): 783–801.PubMedCrossRefGoogle Scholar
  2. Aliberti, J. C., M. A. Cardoso, et al. (1996). “Interleukin-12 mediates resistance to Trypanosoma cruzi in mice and is produced by murine macrophages in response to live trypomastigotes.” Infect Immun 64(6): 1961–7.PubMedGoogle Scholar
  3. Aliberti, J. C., F. S. Machado, et al. (1999). “beta-Chemokines enhance parasite uptake and promote nitric oxide-dependent microbiostatic activity in murine inflammatory macrophages infected with Trypanosoma cruzi.” Infect Immun 67(9): 4819–26.PubMedGoogle Scholar
  4. Almeida, I. C., M. M. Camargo, et al. (2000). “Highly purified glycosylphosphatidylinositols from Trypanosoma cruzi are potent proinflammatory agents.” EMBO J 19(7): 1476–85.PubMedCrossRefGoogle Scholar
  5. Almeida, I. C. and R. T. Gazzinelli (2001). “Proinflammatory activity of glycosylphosphatidylinositol anchors derived from Trypanosoma cruzi: structural and functional analyses.” J Leukoc Biol 70(4): 467–77.PubMedGoogle Scholar
  6. Alvarez, V. E., G. Kosec, et al. (2008). “Blocking autophagy to prevent parasite differentiation: a possible new strategy for fighting parasitic infections?” Autophagy 4(3): 361–3.PubMedGoogle Scholar
  7. Alvarez, V. E., G. Kosec, et al. (2008). “Autophagy is involved in nutritional stress response and differentiation in Trypanosoma cruzi.” J Biol Chem 283(6): 3454–64.PubMedCrossRefGoogle Scholar
  8. Antunez, M. I. and R. L. Cardoni (2000). “IL-12 and IFN-gamma production, and NK cell activity, in acute and chronic experimental Trypanosoma cruzi infections.” Immunol Lett 71(2): 103–9.PubMedCrossRefGoogle Scholar
  9. Araujo-Jorge, T. C., M. C. Waghabi, et al. (2008). “Pivotal role for TGF-beta in infectious heart disease: The case of Trypanosoma cruzi infection and consequent Chagasic myocardiopathy.” Cytokine Growth Factor Rev 19(5–6): 405–13.PubMedCrossRefGoogle Scholar
  10. Bachmann, M. F., M. Kopf, et al. (2006). “Chemokines: more than just road signs.” Nat Rev Immunol 6(2): 159–64.PubMedCrossRefGoogle Scholar
  11. Bafica, A., H. C. Santiago, et al. (2006). “Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruzi infection.” J Immunol 177(6): 3515–9.PubMedGoogle Scholar
  12. Bartholomeu, D. C., C. Ropert, et al. (2008). “Recruitment and endo-lysosomal activation of TLR9 in dendritic cells infected with Trypanosoma cruzi.” J Immunol 181(2): 1333–44.PubMedGoogle Scholar
  13. Calandra, T. and T. Roger (2003). “Macrophage migration inhibitory factor: a regulator of innate immunity.” Nat Rev Immunol 3(10): 791–800.PubMedCrossRefGoogle Scholar
  14. Calzada, J. E., A. Nieto, et al. (2001). “Chemokine receptor CCR5 polymorphisms and Chagas’ disease cardiomyopathy.” Tissue Antigens 58(3): 154–8.PubMedCrossRefGoogle Scholar
  15. Camargo, M. M., I. C. Almeida, et al. (1997). “Glycosylphosphatidylinositol-anchored mucin-like glycoproteins isolated from Trypanosoma cruzi trypomastigotes initiate the synthesis of proinflammatory cytokines by macrophages.” J Immunol 158(12): 5890–901.PubMedGoogle Scholar
  16. Campos, M. A., I. C. Almeida, et al. (2001). “Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite.” J Immunol 167(1): 416–23.PubMedGoogle Scholar
  17. Campos, M. A., M. Closel, et al. (2004). “Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88.” J Immunol 172(3): 1711–8.PubMedGoogle Scholar
  18. Canavaci, A. M., J. M. Bustamante, et al. (2010). ““In vitro and in vivo high-throughput assays for the testing of anti-Trypanosoma cruzi compounds.” PLoS Negl Trop Dis 4(7): e740.PubMedCrossRefGoogle Scholar
  19. Cardillo, F., J. C. Voltarelli, et al. (1996). “Regulation of Trypanosoma cruzi infection in mice by gamma interferon and interleukin 10: role of NK cells.” Infect Immun 64(1): 128–34.PubMedGoogle Scholar
  20. Carrera-Silva, E. A., C. R. Carolina, et al. (2008). “TLR2, TLR4 and TLR9 are differentially modulated in liver lethally injured from BALB/c and C57BL/6 mice during Trypanosoma cruzi acute infection.” Mol Immunol 45(13): 3580–8.PubMedCrossRefGoogle Scholar
  21. de Souza, W., T. M. de Carvalho, et al. (2010). “Review on Trypanosoma cruzi: Host Cell Interaction.” Int J Cell Biol 2010.Google Scholar
  22. DosReis, G. A., C. G. Freire-de-Lima, et al. (2005). “The importance of aberrant T-cell responses in Chagas disease.” Trends Parasitol 21(5): 237–43.PubMedCrossRefGoogle Scholar
  23. El-Sayed, N. M., P. J. Myler, et al. (2005). “The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.” Science 309(5733): 409–15.PubMedCrossRefGoogle Scholar
  24. Epting, C. L., B. M. Coates, et al. (2010). “Molecular mechanisms of host cell invasion by Trypanosoma cruzi.” Exp Parasitol 126(3): 283–91.PubMedCrossRefGoogle Scholar
  25. Freire-de-Lima, C. G., D. O. Nascimento, et al. (2000). “Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages.” Nature 403(6766): 199–203.PubMedCrossRefGoogle Scholar
  26. Gazzinelli, R. T. and E. Y. Denkers (2006). “Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism.” Nat Rev Immunol 6(12): 895–906.PubMedCrossRefGoogle Scholar
  27. Gazzinelli, R. T., I. P. Oswald, et al. (1992). “The microbicidal activity of interferon-gamma-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-beta.” Eur J Immunol 22(10): 2501–6.PubMedCrossRefGoogle Scholar
  28. Guedes, P. M., F. S. Oliveira, et al. (2010). “Nitric oxide donor trans-[RuCl([15]aneN)NO] as a possible therapeutic approach for Chagas’ disease.” Br J Pharmacol 160(2): 270–82.PubMedCrossRefGoogle Scholar
  29. Gutierrez, F. R., M. M. Lalu, et al. (2008). “Increased activities of cardiac matrix metalloproteinases matrix metalloproteinase (MMP)-2 and MMP-9 are associated with mortality during the acute phase of experimental Trypanosoma cruzi infection.” J Infect Dis 197(10): 1468–76.PubMedCrossRefGoogle Scholar
  30. Gutierrez, F. R., T. W. Mineo, et al. (2009). “The effects of nitric oxide on the immune system during Trypanosoma cruzi infection.” Mem Inst Oswaldo Cruz 104 Suppl 1: 236–45.PubMedCrossRefGoogle Scholar
  31. Hirata, N., Y. Yanagawa, et al. (2008). “Selective synergy in anti-inflammatory cytokine production upon cooperated signaling via TLR4 and TLR2 in murine conventional dendritic cells.” Mol Immunol 45(10): 2734–42.PubMedCrossRefGoogle Scholar
  32. Kayama, H. and K. Takeda (2010). “The innate immune response to Trypanosoma cruzi infection.” Microbes Infect 12(7): 511–7.PubMedCrossRefGoogle Scholar
  33. Lee, S. W., H. Choi, Eun, et al. (2011). J Immunol 186(12): 6972–80. Epub 2011 May 9. PMID: 21555530.PubMedCrossRefGoogle Scholar
  34. Lykens, J. E., C. E. Terrell, et al. (2010). “Mice with a selective impairment of IFN-gamma signaling in macrophage lineage cells demonstrate the critical role of IFN-gamma-activated macrophages for the control of protozoan parasitic infections in vivo.” J Immunol 184(2): 877–85.PubMedCrossRefGoogle Scholar
  35. Machado, F. S., N. S. Koyama, et al. (2005). “CCR5 plays a critical role in the development of myocarditis and host protection in mice infected with Trypanosoma cruzi.” J Infect Dis 191(4): 627–36.PubMedCrossRefGoogle Scholar
  36. Manicone, A. M. and J. K. McGuire (2008). “Matrix metalloproteinases as modulators of inflammation.” Semin Cell Dev Biol 19(1): 34–41.PubMedCrossRefGoogle Scholar
  37. Medeiros, M. M., J. R. Peixoto, et al. (2007). “Toll-like receptor 4 (TLR4)-dependent proinflammatory and immunomodulatory properties of the glycoinositolphospholipid (GIPL) from Trypanosoma cruzi.” J Leukoc Biol 82(3): 488–96.PubMedCrossRefGoogle Scholar
  38. Medzhitov, R. (2001). “Toll-like receptors and innate immunity.” Nat Rev Immunol 1(2): 135–45.PubMedCrossRefGoogle Scholar
  39. Mosser, D. M. and J. P. Edwards (2008). “Exploring the full spectrum of macrophage activation.” Nat Rev Immunol 8(12): 958–69.PubMedCrossRefGoogle Scholar
  40. Niedbala, W., J. C. Alves-Filho, et al. (2011). Proc Natl Acad Sci USA. 108(22): 9220–5. Epub 2011 May 16. PMID: 21576463.PubMedCrossRefGoogle Scholar
  41. Oliveira, A. C., B. C. de Alencar, et al. (2010). “Impaired innate immunity in Tlr4(−/−) mice but preserved CD8+ T cell responses against Trypanosoma cruzi in Tlr4-, Tlr2-, Tlr9- or Myd88-deficient mice.” PLoS Pathog 6(4): e1000870.PubMedCrossRefGoogle Scholar
  42. Oliveira, A. C., J. R. Peixoto, et al. (2004). “Expression of functional TLR4 confers proinflammatory responsiveness to Trypanosoma cruzi glycoinositolphospholipids and higher resistance to infection with T. cruzi.” J Immunol 173(9): 5688–96.PubMedGoogle Scholar
  43. Ouaissi, A., E. Guilvard, et al. (2002). “The Trypanosoma cruzi Tc52-released protein induces human dendritic cell maturation, signals via Toll-like receptor 2, and confers protection against lethal infection.” J Immunol 168(12): 6366–74.PubMedGoogle Scholar
  44. Poncini, C. V., C. D. Alba Soto, et al. (2008). “Trypanosoma cruzi induces regulatory dendritic cells in vitro.” Infect Immun 76(6): 2633–41.PubMedCrossRefGoogle Scholar
  45. Reyes, J. L., L. I. Terrazas, et al. (2006). “Macrophage migration inhibitory factor contributes to host defense against acute Trypanosoma cruzi infection.” Infect Immun 74(6): 3170–9.PubMedCrossRefGoogle Scholar
  46. Ropert, C., I. C. Almeida, et al. (2001). “Requirement of mitogen-activated protein kinases and I kappa B phosphorylation for induction of proinflammatory cytokines synthesis by macrophages indicates functional similarity of receptors triggered by glycosylphosphatidylinositol anchors from parasitic protozoa and bacterial lipopolysaccharide.” J Immunol 166(5): 3423–31.PubMedGoogle Scholar
  47. Silva, G. K., F. R. Gutierrez, et al. (2010). “Cutting edge: nucleotide-binding oligomerization domain 1-dependent responses account for murine resistance against Trypanosoma cruzi infection.” J Immunol 184(3): 1148–52.PubMedCrossRefGoogle Scholar
  48. Silva, J. J., W. R. Pavanelli, et al. (2009). “Experimental chemotherapy against Trypanosoma cruzi infection using ruthenium nitric oxide donors.” Antimicrob Agents Chemother 53(10): 4414–21.PubMedCrossRefGoogle Scholar
  49. Silva, J. S., F. S. Machado, et al. (2003). “The role of nitric oxide in the pathogenesis of Chagas disease.” Front Biosci 8: s314-25.PubMedCrossRefGoogle Scholar
  50. Silva, J. S., D. R. Twardzik, et al. (1991). “Regulation of Trypanosoma cruzi infections in vitro and in vivo by transforming growth factor beta (TGF-beta).” J Exp Med 174(3): 539–45.PubMedCrossRefGoogle Scholar
  51. Tarleton, R. L. (2007). “Immune system recognition of Trypanosoma cruzi.” Curr Opin Immunol 19(4): 430–4.PubMedCrossRefGoogle Scholar
  52. Teixeira, M. M., R. T. Gazzinelli, et al. (2002). “Chemokines, inflammation and Trypanosoma cruzi infection.” Trends Parasitol 18(6): 262–5.PubMedCrossRefGoogle Scholar
  53. Torres, O. A., J. E. Calzada, et al. (2009). “Association of the macrophage migration inhibitory factor −173 G/C polymorphism with Chagas disease.” Hum Immunol 70(7): 543–6.PubMedCrossRefGoogle Scholar
  54. Tschopp, J., F. Martinon, et al. (2003). “NALPs: a novel protein family involved in inflammation.” Nat Rev Mol Cell Biol 4(2): 95–104.PubMedCrossRefGoogle Scholar
  55. Une, C., J. Andersson, et al. (2003). “Role of IFN-alpha/beta and IL-12 in the activation of natural killer cells and interferon-gamma production during experimental infection with Trypanosoma cruzi.” Clin Exp Immunol 134(2): 195–201.PubMedCrossRefGoogle Scholar
  56. Zhang, S., C. C. Kim, et al. (2010). “Delineation of diverse macrophage activation programs in response to intracellular parasites and cytokines.” PLoS Negl Trop Dis 4(3): e648.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2012

Authors and Affiliations

  1. 1.School of MedicineAntonio Nariño UniversityBogotáColombia

Personalised recommendations