Autoimmunity and the Paradox of Chagas Disease

  • Ester Roffe
  • Philip M. MurphyEmail author


Chagas disease, also known as American trypanosomiasis, is a vector-borne zoonosis endemic to Latin America that is caused by persistent infection with the protozoan Trypanosoma cruzi. Chagas disease poses a major public health burden to Latin America where it plays out as a ticking time bomb over decades in two stages: an acute stage marked by parasitemia with or without symptoms and a frequently fatal chronic stage that presents in ~one-third of infected individuals as an inflammatory dilated cardiomyopathy and/or inflammatory dilatation of the colon and esophagus. Although T. cruzi has fulfilled Koch’s postulates in Chagas disease, the pathogen burden is typically very low or even undetectable in the chronic stage despite exuberant immunopathology. This paradox has led to an autoimmune theory of pathogenesis that despite intense investigation remains inconclusive and controversial.


Trypanosoma cruzi Cardiomyopathy Zoonosis Cytokine Th1 immunity 



Tumor necrosis factor



This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Disease of the National Institutes of Health.


  1. 1.
    Chagas C. Nova tripanozomiase humana: estudos sobre a morfolojia e o ciclo evolutivo do Schizotrypanum cruzi n. gen., n. sp., ajente etiolojico de nova entidade morbida do homem. Mem Inst Oswaldo Cruz. 1909;1(2):159–218.CrossRefGoogle Scholar
  2. 2.
    Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375(9723):1388–402.CrossRefPubMedGoogle Scholar
  3. 3.
    Koberle F. Aspectos neurológicos da moléstia de chagas. Arq Neuropsiquiatr. 1967;25(3):159–74.CrossRefGoogle Scholar
  4. 4.
    Chagas C. Moléstia de Carlos Chagas ou tireoidite parasitária: nova doença humana transmitida pelo barbeiro. Rev Méd São Paulo. 1911;14:337–56.Google Scholar
  5. 5.
    Franco JR, Simarro PP, Diarra A, Jannin JG. Epidemiology of human African trypanosomiasis. Clin Epidemiol. 2014;6:257–75.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Teixeira ARL, Hecht MM, Guimaro MC, Sousa AO, Nitz N. Pathogenesis of Chagas disease: parasite persistence and autoimmunity. Clin Microbiol Rev. 2011;24:592–630.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Rey L. Parasitologia - Parasitos e doenças parasitárias do homem nas Américas e na África. [Parasites and parasitic diseases of man in the Americas and Africa]. 2nd ed. Rio de Janeiro: Guanabara Koogan; 1991. p. 731.Google Scholar
  8. 8.
    Bern C. Chagas’ disease. N Engl J Med. 2015;373(5):456–66.CrossRefPubMedGoogle Scholar
  9. 9.
    Chagas C. Nova espécie mórbida do homem, produzida por um trypanosoma (Trypanosoma cruzi). Bras Med. 1909;23:161.Google Scholar
  10. 10.
    Scharfstein J, Gomes JAS, Correa-Oliveira R. Back to the future in Chagas disease: from animal models to patient cohort studies, progress in immunopathogenesis research. Mem Inst Oswaldo Cruz. 2009;104(Suppl. 1):187–98.CrossRefPubMedGoogle Scholar
  11. 11.
    Bern C, Montgomery SP, Herwaldt BL, Rassi A Jr, Marin-Neto JA, Dantas RO, Maguire JH, Acquatella H, Morillo C, Kirchhoff LV, Gilman RH, Reyes PA, Salvatella R, Moore AC. Evaluation and treatment of Chagas disease in the United States: a systematic review. JAMA. 2007;298:2171–81.CrossRefPubMedGoogle Scholar
  12. 12.
    GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545–602.CrossRefGoogle Scholar
  13. 13.
    Chagas disease (American trypanosomiasis) Fact sheet N°340. World Health Organization; 2013. Archived from the original on 27 February 2014.
  14. 14.
    GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1459–544.CrossRefGoogle Scholar
  15. 15.
    Montgomery SP, Starr MC, Cantey PT, Edwards MS, Meymandi SK. Neglected parasitic infections in the United States: Chagas disease. Am J Trop Med Hyg. 2014;90(5):814–8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cardoso MS, Reis-Cunha JL, Bartholomeu DC. Evasion of the immune response by Trypanosoma cruzi during acute infection. Front Immunol. 2015;6:659.PubMedGoogle Scholar
  17. 17.
    Teixeira MM, Gazzinelli RT, Silva JS. Chemokines, inflammation and Trypanosoma cruzi infection. Trends Parasitol. 2002;18(6):262–5.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hardison JL, Wrightsman RA, Carpenter PM, Lane TE, Manning JE. The chemokines CXCL9 and CXCL10 promote a protective immune response but do not contribute to cardiac inflammation following infection with Trypanosoma cruzi. Infect Immun. 2006;74(1):125–34.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hardison JL, Kuziel WA, Manning JE, Lane TE. Chemokine CC receptor 2 is important for acute control of cardiac parasitism but does not contribute to cardiac inflammation after infection with Trypanosoma cruzi. J Infect Dis. 2006;193(11):1584–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Machado FS, Koyama NS, Carregaro V, Ferreira BR, Milanezi CM, Teixeira MM, Rossi MA, Silva JS. CCR5 plays a critical role in the development of myocarditis and host protection in mice infected with Trypanosoma cruzi. J Infect Dis. 2005;191(4):627–36.CrossRefPubMedGoogle Scholar
  21. 21.
    Hardison JL, Wrightsman RA, Carpenter PM, Kuziel WA, Lane TE, Manning JE. The CC chemokine receptor 5 is important in control of parasite replication and acute cardiac inflammation following infection with Trypanosoma cruzi. Infect Immun. 2006;74(1):135–43.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Albareda MC, Laucella SA, Alvarez MG, Armenti AH, Bertochi G, Tarleton RL, Postan M. Trypanosoma cruzi modulates the profile of memory CD8+ T cells in chronic Chagas’ disease patients. Int Immunol. 2006;18(3):465–71.CrossRefPubMedGoogle Scholar
  23. 23.
    Bonney KM, Taylor JM, Thorp EB, Epting CL, Engman DM. Depletion of regulatory T cells decreases cardiac parasitosis and inflammation in experimental Chagas disease. Parasitol Res. 2015;114(3):1167–78.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Arguello RJ, Albareda MC, Alvarez MG, Bertocchi G, Armenti AH, Vigliano C, Meckert PC, Tarleton RL, Laucella SA. Inhibitory receptors are expressed by Trypanosoma cruzi-specific effector T cells and in hearts of subjects with chronic Chagas disease. PLoS One. 2012;7(5):e35966.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Andrade SG, Campos RF, Sobral KS, Magalhães JB, Guedes RS, Guerreiro ML. Reinfections with strains of Trypanosoma cruzi, of different biodemes as a factor of aggravation of myocarditis and myositis in mice. Rev Soc Bras Med Trop. 2006;39(1):1–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Pereira ME, Santos LM, Araújo MS, Brener Z. Recrudescence induced by cyclophosphamide of chronic Trypanosoma cruzi infection in mice is influenced by the parasite strain. Mem Inst Oswaldo Cruz. 1996;91(1):71–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Bern C. Chagas disease in the immunosuppressed host. Curr Opin Infect Dis. 2012;25(4):450–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Parodi C, Padilla AM, Basombrío MA. Protective immunity against Trypanosoma cruzi. Mem Inst Oswaldo Cruz. 2009;104(Suppl. I):288–94.CrossRefPubMedGoogle Scholar
  29. 29.
    Bonney K, Engman DM. Autoimmune pathogenesis of Chagas heart disease: looking back, looking ahead. Am J Pathol. 2015;185(6):1537–47.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tarleton RL. Parasite persistence in the aetiology of Chagas disease. Int J Parasitol. 2001;31(5–6):550–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Roffê E, Marino AP, Weaver J, Wan W, de Araújo FF, Hoffman V, Santiago HC, Murphy PM. Trypanosoma cruzi causes paralyzing systemic necrotizing Vasculitis driven by pathogen-specific type I immunity in mice. Infect Immun. 2016;84(4):1123–36.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Higuchi ML, Gutierrez PS, Aiello VD, Palomino S, Bocchi E, Kalil J, Bellotti G, Pileggi F. Immunohistochemical characterization of infiltrating cells in human chronic chagasic myocarditis: comparison with myocardial rejection process. Virchows Arch A Pathol Anat Histopathol. 1993;423(3):157–60.CrossRefGoogle Scholar
  33. 33.
    Gomes JA, Bahia-Oliveira LM, Rocha MO, Martins-Filho OA, Gazzinelli G, Correa-Oliveira R. Evidence that development of severe cardiomyopathy in human Chagas’ disease is due to a Th1-specific immune response. Infect Immun. 2003;71(3):1185–93.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Martin DL, Weatherly DB, Laucella SA, Cabinian MA, Crim MT, Sullivan S, Heiges M, Craven SH, Rosenberg CS, Collins MH, Sette A, Postan M, Tarleton RL. CD8+ T-cell responses to Trypanosoma cruzi are highly focused on strain-variant trans-sialidase epitopes. PLoS Pathog. 2006;2(8):e77.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Rodrigues MM, Alencar BC, Claser C, Tzelepis F. Immunodominance: a new hypothesis to explain parasite escape and host/parasite equilibrium leading to the chronic phase of Chagas’ disease? Braz J Med Biol Res. 2009;42(3):220–3.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Scharfstein J, Andrade D. Infection-associated vasculopathy in experimental chagas disease pathogenic roles of endothelin and kinin pathways. Adv Parasitol. 2011;76:101–27.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Tarleton RL, Zhang L. Chagas disease etiology: autoimmunity or parasite persistence? Parasitol Today. 1999;15:94–9.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi A Jr, Rosas F, Villena E, Quiroz R, Bonilla R, Britto C, Guhl F, Velazquez E, Bonilla L, Meeks B, Rao-Melacini P, Pogue J, Mattos A, Lazdins J, Rassi A, Connolly SJ, Yusuf S, BENEFIT Investigators. Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med. 2015;373(14):1295–306.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Santos-Buch CA, Teixeira AR. The immunology of experimental Chagas’ disease. 3. Rejection of allogeneic heart cells in vitro. J Exp Med. 1974;140(1):38–53.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Borda ES, Sterin-Borda L. Antiadrenergic and muscarinic receptor antibodies in Chagas’ cardiomyopathy. Int J Cardiol. 1996;54(2):149–56.CrossRefPubMedGoogle Scholar
  41. 41.
    Motrán CC, Fretes RE, Cerbán FM, Rivarola HW, Vottero de Cima E. Immunization with the C-terminal region of Trypanosoma cruzi ribosomal P1 and P2 proteins induces long-term duration cross-reactive antibodies with heart functional and structural alterations in young and aged mice. Clin Immunol. 2000;97(2):89–94.CrossRefPubMedGoogle Scholar
  42. 42.
    Cunha-Neto E, Coelho V, Guilherme L, Fiorelli A, Stolf N, Kalil J. Autoimmunity in Chagas’ disease. Identification of cardiac myosin-B13 Trypanosoma cruzi protein crossreactive T cell clones in heart lesions of a chronic Chagas’ cardiomyopathy patient. J Clin Investig. 1996;98(8):1709–12.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Laguens RP, Meckert PC, Chambó JG. Antiheart antibody-dependent cytotoxicity in the sera of mice chronically infected with Trypanosoma cruzi. Infect Immun. 1988;56(4):993–7.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Pontes-de-Carvalho L, Santana CC, Soares MB, Oliveira GG, Cunha-Neto E, Ribeiro-dos-Santos R. Experimental chronic Chagas’ disease myocarditis is an autoimmune disease preventable by induction of immunological tolerance to myocardial antigens. J Autoimmun. 2002;18:131–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Garcia S, Ramos CO, Senra JF, Vilas-Boas F, Rodrigues MM, Campos-de-Carvalho AC, Ribeiro-Dos-Santos R, Soares MB. Treatment with benznidazole during the chronic phase of experimental Chagas’ disease decreases cardiac alterations. Antimicrob Agents Chemother. 2005;49(4):1521–8.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ruiz AM, Esteva M, Cabeza Meckert P, Laguens RP, Segura EL. Protective immunity and pathology induced by inoculation of mice with different subcellular fractions of Trypanosoma cruzi. Acta Trop. 1985;42(4):299–309.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Departamento de Bioquímica e ImunologiaUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  2. 2.Laboratory of Molecular ImmunologyNational Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUSA

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