Skip to main content
Log in

Mechanisms of pathogenesis in Chagas disease

  • Invited Review
  • Published:
Acta Parasitologica Aims and scope Submit manuscript

Abstract

Chagas disease, caused by the obligate unicellular parasite Trypanosoma cruzi, presents itself in a diverse collection of clinical manifestations, ranging from severe, fatal heart and digestive tract pathologies to unapparent or minor alterations that do not compromise survival. Over the years, a number of mechanisms have been proposed to explain the pathogenesis of chagasic tissue lesions, all of which have faced some criticism or been received with skepticism. This article excludes the autoimmunity hypothesis for Chagas disease because it has been extensively reviewed elsewhere, and summarizes the various alternative hypotheses that have been advanced over the years. For each of these hypotheses, an outline of its main tenets and key findings that support them is presented. This is followed by the results and comments that have challenged them and the caveats that stand on their way to wider acceptance. It is hoped that this writing will draw attention to our shortcomings in understanding the pathogenesis of Chagas disease, which, unfortunately, continues to figure among the most serious health problems of the American continent.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Amorim D.S., Manço J.C., Gallo L., Marin Neto J.A. 1979. Clinica: forma cronica cardíaca. In: Trypoanosoma cruzi e Doença de Chagas (Eds. Z. Brener and Z.A. Andrade). Guanabara Koogan, Rio de Janeiro, 265–311.

    Google Scholar 

  • Amorim D.S., Olsen E.G. 1982. Assessment of heart neurons in dilated (congestive) cardiomyopathy. British Heart Journal, 47, 11–18.

    PubMed  CAS  Google Scholar 

  • Andrade Z.A. 1999. Immunopathology of Chagas disease. Memorias do Instituto Oswaldo Cruz, 94,Suppl. 1, 71–80.

    PubMed  Google Scholar 

  • Andrade S.G., Magalhaes J.B. 1996. Biodemes and zymodemes of Trypanosoma cruzi strains: correlations with clinical data and experimental pathology. Revista do Sociedad Brasileira de Medicina Tropical, 30, 27–35.

    CAS  Google Scholar 

  • Andrade S.G., Pimentel A.R., Souza M.M. de, Andrade Z.A. 2000. Interstitial dendritic cells of the heart harbor Trypanosoma cruzi antigens in experimentally infected dogs: importance for the pathogenesis of chagasic myocarditis. American Journal of Tropical Medicine and Hygiene, 63, 64–70.

    PubMed  CAS  Google Scholar 

  • Andrade Z.A., Andrade S.G. 1979. Patologia. In: Trypanosoma cruzi e Doença de Chagas (Eds. Z. Brener and Z.A. Andrade). Guanabara Koogan, Rio de Janeiro, 199–248.

    Google Scholar 

  • Andrade Z.A., Andrade S.G., Correa R., Sadigursky M., Ferrans V.J. 1994. Myocardial changes in acute Trypanosoma cruzi infection — ultrastructural evidence of immune damage and the role of microangiopathy. American Journal of Pathology, 144, 1403–1411.

    PubMed  CAS  Google Scholar 

  • Araujo-Jorge T.C. de 1989. The biology of Trypanosoma cruzi-macrophage interaction. Memorias do Instituto Oswaldo Cruz, 84, 441–462.

    PubMed  Google Scholar 

  • Avila J.L. 1992. Molecular mimicry between Trypanosoma cruzi and host nervous tissues. Acta Científica Venezolana, 43, 330–340.

    PubMed  CAS  Google Scholar 

  • Barcinski M.A., DosReis G.A. 1999. Apoptosis in parasites and parasite-induced apoptosis in the host immune system: a new approach to parasitic diseases. Brazilian Journal of Biological Research, 32, 395–401.

    CAS  Google Scholar 

  • Barnabe C., Neubauer K., Solari A., Tibayrenc M. 2001. Trypanosoma cruzi: presence of the two major phylogenetic lineages and of several lesser discrete typing units (DTUs) in Chile and Paraguay. Acta Tropica, 78, 127–137.

    Article  PubMed  CAS  Google Scholar 

  • Benvenuti L.A., Aiello V.D., Palomino S.A., Higuchi M.L. 2003. Ventricular expression of atrial natriuretic peptide in chronic chagasic cardiomyopathy is not induced by myocarditis. International Journal of Cardiology, 88, 57–61.

    Article  PubMed  Google Scholar 

  • Bestetti R.B., Coutinho-Neto J., Staibano L., Pinto L.Z., Muccillo G., Oliveira J.S. 1995. Peripheral and coronary sinus catecholamine levels in patients with severe congestive heart failure due to Chagas’ disease. Cardiology, 86, 202–206.

    PubMed  CAS  Google Scholar 

  • Bijovsky A.T., Milder R.V., Abrahamson I.A., Sinhorini I.L., Mariano M. 1984. The influence of lymphatic drainage in experimental Trypanosoma cruzi infection. Acta Tropica, 41, 207–214.

    PubMed  CAS  Google Scholar 

  • Bogliolo A.R., Lauria-Pires L., Gibson W.C. 1996. Polymorphisms in Trypanosoma cruzi: Evidence of genetic recombination. Acta Tropica, 61, 31–40.

    Article  PubMed  CAS  Google Scholar 

  • Brener Z., Andrade Z.A. 1979. Trypanosoma cruzi e Doença de Chagas. Guanabara Koogan, Rio de Janeiro.

    Google Scholar 

  • Brener Z., Gazzinelli R.T. 1997. Immunological control of Trypanosoma cruzi infection and pathogenesis of Chagas’ disease. International Archives of Allergy and Immunology, 114.

  • Bruggink A.H., Jonge N. de, Oosterhout M.F. van, Wichen D.F. van, Koning E. de, Lahpor J.R., Kemperman H., Gmelig-Meyling F.H., Weger R.A. de 2006. Brain natriuretic peptide is produced both by cardiomyocytes and cells infiltrating the heart in patients with severe heart failure supported by a left ventricular assist device. Journal of Heart and Lung Transplantation, 25, 174–180.

    Article  PubMed  Google Scholar 

  • Buscaglia C.A., Di Noia J.M. 2003. Trypanosoma cruzi clonal diversity and the epidemiology of Chagas’ disease. Microbes and Infection, 5, 419–427.

    Article  PubMed  CAS  Google Scholar 

  • Caeiro T.F., Palmero H.A., Iosa D. 1980. Baroreceptor reflex in Chagas disease. Medicina (Buenos Aires), 40,Suppl. 1, 27–32.

    Google Scholar 

  • Cardarelli R., Lumicao T.C. Jr. 2003. B-type natriuretic peptide: a review of its diagnostic, prognostic, and therapeutic monitoring value in heart failure for primary care physicians. Journal of the American Board of Family Practice, 16, 327–333.

    PubMed  Google Scholar 

  • Campbell D.A., Westenberger S.J., Sturm N.R. 2004. The determinants of Chagas disease: connecting the parasite and host genetics. Current Molecular Medicine, 4, 549–562.

    Article  PubMed  CAS  Google Scholar 

  • Carrasco Guerra H.A., Palacios-Pru E., Dagert de Scorza C., Molina C., Inglessis G., Mendoza R.V. 1987. Clinical, histochemical, and ultrastructural correlation in septal endomyocardial biopsies from chronic chagasic patients: detection of early myocardial damage. American Heart Journal, 113, 716–724.

    Article  PubMed  CAS  Google Scholar 

  • Carrasco H.J., Frame I.A., Valente S.A., Miles M.A. 1996. Genetic exchange as a possible source of genomic diversity in sylvatic populations of Trypanosoma cruzi. American Journal of Tropical Medicine and Hygiene, 54, 418–424.

    PubMed  CAS  Google Scholar 

  • Castagnino H.E., Jorg M.E., Thompson A.C. 1982. Ventricular aneurysms in chronic Chagas’ cardiopathy. Journal of Cardiovascular Surgery (Torino), 23, 28–33.

    CAS  Google Scholar 

  • Chagas C. 1909. Nova trypanosomíase humana. Estudos sobre a morfologia e o ciclo evolutivo do Schizotrypanum cruzi n. gen., n. sp., agente etiológico de nova entidade morbida do homem. Memorias do Instituto Oswaldo Cruz, 1, 159–218.

    Google Scholar 

  • Chen Q., Vazquez E.J., Moghaddas S., Hoppel C.L., Lesnefsky E.J. 2003. Production of reactive oxygen species by mitochondria: central role of complex III. Journal of Biological Chemistry, 278, 36027–36031.

    Article  PubMed  CAS  Google Scholar 

  • Cohn J.N., Ferrari R., Sharpe N. 2000. Cardiac remodeling — concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. Journal of the American College of Cardiology, 35, 569–582.

    Article  PubMed  CAS  Google Scholar 

  • Coronado X., Zulantay I., Albrecht H., Rozas M., Apt W., Ortiz S., Rodriguez J., Sanchez G., Solari A. 2006. Variation in Trypanosoma cruzi clonal composition detected in blood patients and xenodiagnosis triatomines: implications in the molecular epidemiology of Chile. American Journal of Tropical Medicine and Hygiene, 74, 1008–1012.

    PubMed  CAS  Google Scholar 

  • Cunha-Neto E., Rizzo L.V., Albuquerque F., Abel L., Guilherme L., Bocchi E., Bacal F., Carrara D., Ianni B., Mady C., Kalil J. 1998. Cytokine production profile of heart-infiltrating T cells in Chagas’ disease cardiomyopathy. Brazilian Journal of Medical and Biological Research, 31, 133–137.

    Article  PubMed  CAS  Google Scholar 

  • D’Angelo-Mendoza E., Rodrigues-Bonfante C., Camacho I., Martinez J., Perdomo T., Cabrera A., Bonfante-Cabarcas R. 2005. Patients suffering dilated chagasic cardiopathy or non chagasic cardiopathy show an increased levels of tumor necrosis factor alpha. Investigación Clínica, 46, 229–240.

    PubMed  Google Scholar 

  • Davila D.F., Angel F., Arata de Bellabarba G., Donis J.H. 2002. Effects of metoprolol in chagasic patients with severe congestive heart failure. International Journal of Cardiology, 85, 255–260.

    Article  PubMed  Google Scholar 

  • Davila D.F., Donis J.H., Torres A., Ferrer J.A. 2004. A modified and unifying neurogenic hypothesis can explain the natural history of chronic Chagas heart disease. International Journal of Cardiology, 96, 191–195.

    Article  PubMed  Google Scholar 

  • Davila D.F., Inglessis G., Mazei de Davila C.A. 1998. Chagas’ disease and the autonomic nervous system. International Journal of Cardiology, 66, 123–127.

    Article  PubMed  CAS  Google Scholar 

  • Davila D.F., Rossell R.O., Donis J.H. 1989. Cardiac parasympathetic abnormalities: Cause or consequence of Chagas heart disease. Parasitology Today, 5, 327–329.

    Article  PubMed  CAS  Google Scholar 

  • Devera R., Fernandes O., Coura J.R. 2003. Should Trypanosoma cruzi be called “cruzi” complex? a review of the parasite diversity and the potential of selecting population after in vitro culturing and mice infection. Memorias do Instituto Oswaldo Cruz, 98,Suppl. 1, 1–12.

    PubMed  CAS  Google Scholar 

  • Dhalla N.S., Temsah R.M., Netticadan T. 2000. Role of oxidative stress in cardiovascular diseases. Journal of Hypertension, 18, 655–673.

    Article  PubMed  CAS  Google Scholar 

  • DosReis G.A., Fonseca M.E.F., Lopes M.F. 1995. Programmed T-cell death in experimental Chagas disease. Parasitology Today, 11, 390–394.

    Article  Google Scholar 

  • DosReis G.A., Barcinski M.A. 2001. Apoptosis and parasitism: from the parasite to the host immune response. Advances in Parasitology, 49, 133–161.

    PubMed  CAS  Google Scholar 

  • Eisen H., Kahn S. 1991. Mimicry in Trypanosoma cruzi — fantasy and reality. Current Opinion in Immunology, 3, 507–510.

    Article  PubMed  CAS  Google Scholar 

  • Elizari M.V. 1999. Chagasic myocardiopathy: historical perspective. Medicina (Buenos Aires), 59,Suppl. 2, 25–40.

    Google Scholar 

  • Elizari M.V. 2002. Arrhythmias associated with Chagas’ heart disease. Cardiac Electrophysiology Review, 6, 115–119.

    Article  PubMed  Google Scholar 

  • Factor S.M., Cho S., Wittner M., Tanowitz H. 1985. Abnormalities of the coronary microcirculation in acute murine Chagas’ disease. American Journal of Tropical Medicine and Hygiene, 34, 246–252.

    PubMed  CAS  Google Scholar 

  • Factor S.M., Minase T., Bhan R., Wolinsky H., Sonnenblick E.H. 1983. Hypertensive diabetic cardiomyopathy in the rat: ultrastructural features. Virchows Archiv. A, Pathological Anatomy and Histopathology, 398, 305–317.

    Article  PubMed  CAS  Google Scholar 

  • Fernandes O., Souto R.P., Castro J.A., Pereira J.B., Fernandes N.C., Junqueira A.C., Naiff R.D., Barrett T.V., Degrave W., Zingales B., Campbell D.A., Coura J.R. 1998. Brazilian isolates of Trypanosoma cruzi from humans and triatomines classified into two lineages using mini-exon and ribosomal RNA sequences. American Journal of Tropical Medicine and Hygiene, 58, 807–811.

    PubMed  CAS  Google Scholar 

  • Fernandez A., Hontebeyrie M., Said G. 1992. Autonomic neuropathy and immunological abnormalities in Chagas’ disease. Clinical Autonomic Research, 2, 409–412.

    Article  PubMed  CAS  Google Scholar 

  • Fuenmayor C., Higuchi M.L., Carrasco H., Parada H., Gutierrez P., Aiello V., Palomino S. 2005. Acute Chagas’ disease: immunohistochemical characteristics of T cell infiltrate and its relationship with T. cruzi parasitic antigens. Acta Cardiologica, 60, 33–37.

    Article  PubMed  Google Scholar 

  • Furumoto T., Fujii S., Mikami T., Inoue M., Nishihara K., Kaga S., Imagawa S., Goto K., Komuro K., Yamada S., Onozuka H., Kitabatake A., Sobel B.E. 2006. Increased plasma concentrations of N-terminal pro-brain natriuretic peptide reflect the presence of mildly reduced left ventricular diastolic function in hypertension. Coronary Artery Disease, 17, 45–50.

    Article  PubMed  Google Scholar 

  • Gaunt M.W., Yeo M., Frame I.A., Stothard J.R., Carrasco H.J., Taylor M.C., Mena S.S., Veazey P., Miles G.A., Acosta N., Arias A.R. de, Miles M.A. 2003. Mechanism of genetic exchange in American trypanosomes. Nature, 421, 936–939.

    Article  PubMed  CAS  Google Scholar 

  • Gavin J.B., Maxwell L., Edgar S.G. 1998. Microvascular involvement in cardiac pathology. Journal of Molecular and Cellular Cardiology, 30, 2531–2540.

    Article  PubMed  CAS  Google Scholar 

  • Gironés N., Cuervo H., Fresno M. 2005. Trypanosoma cruzi-induced molecular mimicry and Chagas’ disease. Current Topics in Microbiology and Immunology, 296, 89–123.

    Article  PubMed  Google Scholar 

  • Gironés N., Fresno M. 2003. Etiology of Chagas disease myocarditis: autoimmunity, parasite persistence, or both? Trends in Parasitology, 19, 19–22.

    Article  PubMed  Google Scholar 

  • Guevara A.G., Eras J.W., Recalde M., Vinueza L., Cooper V.J., Ouaissi A., Guderian R.H. 1997. Severe digestive pathology associated with chronic Chagas’ disease in Ecuador: report of two cases. Revista da Sociedad Brasileira de Medicina Tropical, 30, 389–392.

    CAS  Google Scholar 

  • Hardison J.L., Wrightsman R.A., Carpenter P.M., Lane T.E., Manning J.E. 2006a. The chemokines CXCL9 and CXCL10 promote a protective immune response but do not contribute to cardiac inflammation following infection with Trypanosoma cruzi. Infection and Immunity, 74, 125–134.

    Article  PubMed  CAS  Google Scholar 

  • Hardison J.L., Wrightsman R.A., Carpenter P.M., Kuziel W.A., Lane T.E., Manning J.E. 2006b. The CC chemokine receptor 5 is important in control of parasite replication and acute cardiac inflammation following infection with Trypanosoma cruzi. Infection and Immunity, 74, 135–143.

    Article  PubMed  CAS  Google Scholar 

  • Higuchi M. 1995. Endomyocardial biopsy in Chagas’ heart disease. São Paulo Medical Journal, 113, 821–825.

    PubMed  CAS  Google Scholar 

  • Higuchi M.L., Benvenuti L.A., Reis M.M., Metzger M. 2003. Pathophysiology of the heart in Chagas’ disease: current status and new developments. Cardiovascular Research, 60, 96–107.

    Article  CAS  Google Scholar 

  • Ide T., Tsutsui H., Kinugawa S., Utsumi H., Kang D., Hattori N., Uchida K., Arimura K., Egashira K., Takeshita A. 1999. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circulation Research, 85, 357–363.

    PubMed  CAS  Google Scholar 

  • Jelicks L.A., Chandra M., Shirani J., Shtutin V., Tang B., Christ G.J., Factor S.M., Wittner M., Huang H., Weiss L.M., Mukherjee S., Bouzahzah B., Petkova S.B., Teixeira M.M., Douglas S.A., Loredo M.L., D’Orleans-Juste P., Tanowitz H.B. 2003. Cardioprotective effects of phosphoramidon on myocardial structure and function in murine Chagas’ disease. International Journal for Parasitology, 33, 217.

    Article  Google Scholar 

  • Junqueira L.F.Jr., Gallo L.Jr., Manco J.C., Marin-Neto J.A., Amorim D.S. 1985. Subtle cardiac autonomic impairment in Chagas’ disease detected by baroreflex sensitivity testing. Brazilian Journal of Biological Research, 18, 171–178.

    Google Scholar 

  • Junqueira L.F., Soares J.D. 2002. Impaired autonomic control of heart interval changes to Valsalva manoeuvre in Chagas’ disease without overt manifestation. Autonomic Neuroscience, 97, 59–67.

    Article  PubMed  Google Scholar 

  • Kalil J., Cunha-Neto E. 1996. Autoimmunity in Chagas disease cardiomyopathy: Fulfilling the criteria at last? Parasitology Today, 12, 396–399.

    Article  PubMed  CAS  Google Scholar 

  • Kedziersky R.M., Yanagisawa M. 2001. Endothelin system: the double-edged sword in health and disease. Annual Review of Pharmacology and Toxicology, 41, 851–876.

    Article  Google Scholar 

  • Kierszenbaum F. 1986. Autoimmunity in Chagas’ disease. Journal of Parasitology, 72, 201–211.

    Article  PubMed  CAS  Google Scholar 

  • Kierszenbaum F. 1999. Chagas’ disease the autoimmunity hypothesis. Clinical Microbiology Reviews, 12, 210–223.

    PubMed  CAS  Google Scholar 

  • Kierszenbaum F. 2003. Views on the autoimmunity hypothesis for Chagas disease pathogenesis. FEMS Immunology and Medical Microbiology, 37, 1–11.

    Article  PubMed  CAS  Google Scholar 

  • Kierszenbaum F. 2005. Where do we stand on the autoimmunity hypothesis of Chagas disease? Trends in Parasitology, 21, 513–516.

    Article  PubMed  CAS  Google Scholar 

  • Kierszenbaum F., Ackerman S.J., Gleich G.J. 1981. Destruction of bloodstream forms of Trypanosoma cruzi by eosinophil granule major basic protein. American Journal of Tropical Medicine and Hygiene, 30, 775–779.

    PubMed  CAS  Google Scholar 

  • Kierszenbaum F., Knecht E., Budzko D.B., Pizzimenti M.C. 1974. Phagocytosis: a defense mechanism against infection with Trypanosoma cruzi. Journal of Immunology, 112, 1839–1844.

    CAS  Google Scholar 

  • Kierszenbaum F., Villalta F., Tai P.-C. 1986. Role of inflammatory cells in Chagas’ disease. III. Kinetics of human eosinophil activation upon interaction with parasites Trypanosoma cruzi. Journal of Immunology, 136, 662–666.

    CAS  Google Scholar 

  • Kirchhoff L.V., Weiss L.M., Wittner M., Tanowitz H.B. 2004. Parasitic diseases of the heart. Frontiers in Bioscience, 9, 706–723.

    Article  PubMed  Google Scholar 

  • Kiss D.R., Habr-Gama A., Pinotti H.W. 1986. Chagas’ megacolon: considerations on new physiopathological perspectives. Revista Paulista de Medicina, 104, 145–155.

    PubMed  CAS  Google Scholar 

  • Klessig D.F., Chow L.T. 1980. Incomplete splicing and deficient accumulation of fiber messenger RNA on monkey cells infected by human adenovirus type 2. Journal of Molecular Biology, 139, 221–242.

    Article  PubMed  CAS  Google Scholar 

  • Köberle F. 1958. Cardiopatia Chagásica. Hospital (Rio de Janeiro), 53, 311–346.

    Google Scholar 

  • Köberle F. 1961. Pathology and pathological anatomy of Chagas’ disease. Boletín de la Oficina Sanitaria Panamericana, 51, 404–428.

    PubMed  Google Scholar 

  • Köberle F. 1974. Pathogenesis of Chagas’ disease. Ciba Foundation Symposium, 20, 137–152.

    Google Scholar 

  • Kuhn R.E. 1994. Macrophages in experimental Chagas’ disease. Immunology Series, 60, 495–502.

    PubMed  CAS  Google Scholar 

  • Leguizamon M.S., Mocetti E., García-Rivello H., Argibay P., Campetella O. 1999. Trans-sialidase from Trypanosoma cruzi induces apoptosis in cells from the immune system in vivo. Journal of Infectious Diseases, 180, 1398–1402.

    Article  PubMed  CAS  Google Scholar 

  • Leon W., Engman D.M. 2001. Autoimmunity in Chagas heart disease. International Journal for Parasitology, 31, 555–561.

    Article  PubMed  CAS  Google Scholar 

  • Leon J.S., Engman D.M. 2002. The contribution of autoimmunity to Chagas heart disease. In: World class parasites: American trypanosomiasis (Eds. K.M. Tyler and M.A. Miles). Kluwer Academic Publishers, New York, 97–106.

    Google Scholar 

  • Lopes A.F., DosReis G.A. 2000. Experimental Chagas disease: phagocytosis of apoptotic lymphocytes deactivates macrophages and fuels parasite growth. Apoptosis, 5, 221–224.

    Article  PubMed  CAS  Google Scholar 

  • Macedo A.M., Machado C.R., Oliveira R.P., Pena S.D.J. 2004. Trypanosoma cruzi: genetic structure of populations and relevance of genetic variability to the pathogenesis of Chagas disease. Memorias do Instituto Oswaldo Cruz, 99,Suppl. 1, 1–12.

    PubMed  CAS  Google Scholar 

  • Macedo V. 1999. Indeterminate form of Chagas disease. Memorias do Instituto Oswaldo Cruz, 94,Suppl. 1, 311–316.

    PubMed  Google Scholar 

  • Machado F.S., Koyama N.S., Carregaro V., Ferreira B.R., Milanezi C.M., Teixeira M.M., Rossi M.A., Silva J.S. 2005. CCR5 plays a critical role in the development of myocarditis and host protection in mice infected with Trypanosoma cruzi. Journal of Infectious Diseases, 191, 627–636.

    Article  PubMed  CAS  Google Scholar 

  • Machado F.S., Martins G.A., Aliberti J.C.S., Mestriner F.L.A.C., Cunha F.Q., Silva J.S. 2000. Trypanosoma cruzi — infected cardiomyocytes produce chemokines and cytokines that trigger potent nitric oxide — dependent trypanocidal activity. Circulation, 102, 3003–3008.

    PubMed  CAS  Google Scholar 

  • Maeda K., Tsutamoto T., Wada A., Hisanaga T., Kinoshita M. 1998. Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction. American Heart Journal, 135, 825–832.

    Article  PubMed  CAS  Google Scholar 

  • Marin-Neto J.A., Marzullo P., Marcassa C., Gallo L.Jr., Maciel B.C., Bellina C.R., L’Abbate A. 1992. Myocardial perfusion abnormalities in chronic Chagas’ disease as detected by Thallium-201 scintigraphy. American Journal of Cardiology, 69, 780–784.

    Article  PubMed  CAS  Google Scholar 

  • Marin-Neto J.A., Simoes M.V., Ayres-Neto E.M., Attab-Santos J.L., Gallo L.Jr., Amorim D.S., Maciel B.C. 1995. Studies of the coronary circulation in Chagas’ heart disease. Revista Paulista de Medicina, 113, 826–834.

    PubMed  CAS  Google Scholar 

  • McDaniel J.P., Dvorak J.A. 1993. Identification, isolation, and characterization of naturally-occurring Trypanosoma cruzi variants. Molecular and Biochemical Parasitology, 57, 213–222.

    Article  PubMed  CAS  Google Scholar 

  • Mengel J.O., Rossi M.A. 1992. Chronic chagasic myocarditis pathogenesis: dependence on autoimmune and microvascular factors. American Heart Journal, 124, 1052–1057.

    Article  PubMed  CAS  Google Scholar 

  • Molina H.A., Kierszenbaum F. 1987. A study of human myocardial tissue in Chagas’ disease: distribution and frequency of inflammatory cell types. International Journal for Parasitology, 17, 1297–1305.

    Article  PubMed  CAS  Google Scholar 

  • Molina H.A., Kierszenbaum F. 1988a. Immunohistochemical detection of deposits of eosinophil-derived neurotoxin and eosinophil peroxidase in the myocardium of patients with Chagas’ disease. Immunology, 64, 725–731.

    PubMed  CAS  Google Scholar 

  • Molina H.A., Kierszenbaum F. 1988b. Kinetics of development of inflammatory lesions in myocardial and skeletal muscle in experimental Trypanosoma cruzi infection. Journal of Parasitology, 74, 370–374.

    Article  PubMed  CAS  Google Scholar 

  • Molina H.A., Kierszenbaum F. 1989a. Eosinophil activation in acute and chronic chagasic myocardial lesions and deposition of toxic eosinophil granule proteins on heart myofibers. Journal of Parasitology, 75, 129–133.

    Article  PubMed  CAS  Google Scholar 

  • Molina H.A., Kierszenbaum F. 1989b. Interaction of human eosinophils or neutrophils with Trypanosoma cruzi in vitro caused bystander cardiac cell damage. Immunology, 66, 289–295.

    PubMed  CAS  Google Scholar 

  • Molina H.A., Kierszenbaum F., Hamann K.J., Gleich G.J. 1988. Toxic effects produced or mediated by human eosinophil granule components on Trypanosoma cruzi. American Journal of Tropical Medicine and Hygiene, 38, 327–334.

    PubMed  CAS  Google Scholar 

  • Morris S.A., Tanowitz H.B., Makman M. 1992. Trypanosoma cruzi: alteration of cAMP metabolism following infection of human endothelial cells. Experimental Parasitology, 74, 69–76.

    Article  PubMed  CAS  Google Scholar 

  • Morris S.A., Bilezikian J.P., Hatcher V., Weiss L.M., Tanowitz H.B., Wittner M. 1989. Trypanosoma cruzi: Infection of cultured human endothelial cells alters inositol phosphate synthesis. Experimental Parasitology, 69, 330–339.

    Article  PubMed  CAS  Google Scholar 

  • Morris S.A., Tanowitz H., Hatcher V., Bilezikian J.P., Wittner M. 1988. Alterations in intracellular calcium following infection of human endothelial cells with Trypanosoma cruzi. Molecular and Biochemical Parasitology, 29, 213–221.

    Article  PubMed  CAS  Google Scholar 

  • Morris S.A., Tanowitz H.B., Wittner M., Bilezikian J.P. 1990. Pathophysiological insights into the cardiomyopathy of Chagas’ disease. Circulation, 82, 1900–1909.

    PubMed  CAS  Google Scholar 

  • Mucci J., Hidalgo A., Mocetti E., Argibay P.F., Leguizamon M.S., Campetella O. 2002. Thymocyte depletion in Trypanosoma cruzi infection is mediated by trans-sialidase-induced apoptosis on nurse cells complex. Proceedings of the National Academy of Sciences, USA, 99, 3896–3901.

    Article  CAS  Google Scholar 

  • Nabors G.S., Tarleton R.L. 1991. Differential control of IFN-gamma and IL-2 production during Trypanosoma cruzi infection. Journal of Immunology, 146, 3591–3598.

    CAS  Google Scholar 

  • Odreman R.O., Davila D.F., Donis J.H., Torres A., Ferrer J., Inglessis I. 2004. Valsalva maneuver in chagasic patients with documented past medical history of acute chagasic myocarditis. International Journal of Cardiology, 93, 163–167.

    Article  PubMed  Google Scholar 

  • Oliveira J.S.M. 1985. A natural human model of intrinsic heart nervous system denervation: Chagas’ cardiopathy. American Heart Journal, 110, 1092–1098.

    Article  PubMed  CAS  Google Scholar 

  • Oliveira J.S.M., Monteiro dos Santos J.C., Muccillo G., Ferreira A.L. 1985. Increased capacity of the coronary arteries in chronic Chagas’ heart disease: further support for the neurogenic pathogenesis concept. American Heart Journal, 109, 304–308.

    Article  PubMed  CAS  Google Scholar 

  • Oliveira-Marques D.S. de, Bonametti A.S., Matsuo T., Gregori Junior F. 2005. The epidemiologic profile and prevalence of cardiopathy in Trypanosoma cruzi infected blood donor candidates, Londrina, Parana, Brazil. Revista do Instituto de Medicina Tropical de São Paulo, 47, 321–326.

    PubMed  Google Scholar 

  • Oliveira R.P., Chiari E., Pena S.D., Macedo A.M. 1997. An alternative approach to evaluating the intraspecific genetic variability of parasites. Parasitology Today, 13, 196–200.

    Article  PubMed  CAS  Google Scholar 

  • Parada H., Carrasco H.A., Anez N., Fuenmayor C., Inglessis I. 1997. Cardiac involvement is a constant finding in acute Chagas’ disease: a clinical, parasitological and histopathological study. International Journal of Cardiology, 60, 49–54.

    Article  PubMed  CAS  Google Scholar 

  • Perlowagora-Szumlewicz A., Muller C.A., Moreira C.J. 1990. Studies in search of a suitable experimental insect model for xenodiagnosis of hosts with Chagas’ disease. 4. The reflection of parasite stock in the responsiveness of different vector species to chronic infection with different Trypanosoma cruzi stocks. Revista de Saúde Pública, 24, 165–177.

    PubMed  CAS  Google Scholar 

  • Petkova S.B., Huang H., Factor S.M., Pestell R.G., Bouzahzah B., Jelicks L.A., Weiss L.M., Douglas S.A., Wittner M., Tanowitz H.B. 2001. The role of endothelin in the pathogenesis of Chagas’ disease. International Journal for Parasitology, 31, 499–511.

    Article  PubMed  CAS  Google Scholar 

  • Piazza L.A., Bold A.J. de, Santamarina N., Hliba E., Rubiolo E.R. 1994. Atrial natriuretic factor in experimental acute Chagas’ disease. Parasitology Research, 80, 78–80.

    Article  PubMed  CAS  Google Scholar 

  • Pinto Dias J.C. 1979. Mecanismos de transmissão. In: Trypanosoma cruzi e Doença de Chagas (Eds. Z. Brener and Z.A. Andrade). Guanabara Koogan, Rio de Janeiro, 152–174.

    Google Scholar 

  • Pompilio M.A., Dorval M.E., Cunha R.V., Britto C., Borges-Pereira J. 2005. Epidemiological, clinical and parasitological aspects of Chagas’ disease in Mato Grosso do Sul State. Revista da Sociedade Brasileira de Medicina Tropical, 38, 473–478.

    Article  PubMed  Google Scholar 

  • Ramos S.G., Rossi M.A. 1999. Microcirculation and Chagas’ disease: hypothesis and recent results. Revista do Instituto de Medicina Tropical de São Paulo, 41, 123–129.

    PubMed  CAS  Google Scholar 

  • Rassi A. 1979. Clinica: fase aguda. In: Trypanosoma cruzi e Doença de Chagas (Eds. Z. Brener and Z.A. Andrade). Guanabara Koogan, Rio de Janeiro, 249–264.

    Google Scholar 

  • Rassi A.Jr., Rassi A., Little W.C. 2000. Chagas’ heart disease. Clinical Cardiology, 23, 883–889.

    Article  PubMed  Google Scholar 

  • Reed S.G. 1988. In vivo administration of recombinant IFN-γ induces macrophage activation, and prevents acute disease, immune suppression, and death in experimental Trypanosoma cruzi infections. Journal of Immunology, 140, 4342–4347.

    CAS  Google Scholar 

  • Rezende J.M. de 1979. Clínica: Manifestaçoes digestivas. In: Trypanosoma cruzi e Doença de Chagas (Eds. Z. Brener and Z.A. Andrade). Guanabara Koogan, Rio de Janeiro, 312–361.

    Google Scholar 

  • Ribeiro A.L., DosReis A.M., Barros M.V., Souza M.R. de, Rocha A.L., Perez A.A., Pereira J.B., Machado F.S., Rocha M.O. 2002. Brain natriuretic peptide and left ventricular dysfunction in Chagas’ disease. Lancet, 360, 461–462.

    Article  PubMed  CAS  Google Scholar 

  • Rocha M.O., Ribeiro A.L., Teixeira M.M. 2003. Clinical management of chronic Chagas cardiomyopathy. Frontiers in Bioscience, 8, e44–e54.

    Article  PubMed  Google Scholar 

  • Romaña C. 1963. Enfermedad de Chagas. Lopez Libreros Editores, Buenos Aires.

    Google Scholar 

  • Rossi M.A. 1990. Microvascular changes as a cause of chronic cardiomyopathy in Chagas’ disease. American Heart Journal, 120, 233–236.

    Article  PubMed  CAS  Google Scholar 

  • Rossi M.A. 1997. Aortic endothelial cell changes in the acute septicemic phase of experimental Trypanosoma cruzi infection in rats: scanning and transmission electron microscopy study. American Journal of Tropical Medicine and Hygiene, 57, 321–327.

    PubMed  CAS  Google Scholar 

  • Rossi M.A., Gonçalves S., Ribeiro-dos-Santos R. 1984. Experimental Trypanosoma cruzi cardiomyopathy in BALB/c mice. The potential role of intravascular platelet aggregation in its genesis. American Journal of Pathology, 114, 209–216.

    PubMed  CAS  Google Scholar 

  • Rossi M.A., Ramos S.G., Bestetti R.B. 1996. Coronary microvascular abnormalities in Chagas’ disease. American Heart Journal, 132, 207–210.

    Article  PubMed  CAS  Google Scholar 

  • Rossi M.A., Souza A.C. 1999. Is apoptosis a mechanism of cell death of cardiomyocytes in chronic chagasic myocarditis? International Journal of Cardiology, 68, 325–331.

    Article  PubMed  CAS  Google Scholar 

  • Russo N., Starobinas N. 1991. Macrophage activation and resistance to Trypanosoma cruzi infection. Research in Immunology, 142, 144–146.

    Article  PubMed  CAS  Google Scholar 

  • Sawyer D.B., Siwik D.A., Xiao L., Pimentel D.R., Singh K., Colucci W.S. 2002. Role of oxidative stress in myocardial hypertrophy and failure. Journal of Molecular and Cellular Cardiology, 34, 379–388.

    Article  PubMed  CAS  Google Scholar 

  • Silva J.S., Machado F.S., Martins G.A. 2003. The role of nitric oxide in the pathogenesis of Chagas disease. Frontiers in Bioscience, 8, e314–e325.

    Article  Google Scholar 

  • Silva J.S., Morrissey P.J., Grabstein K.H., Mohler K.M., Anderson D., Reed S.G. 1992. Interleukin-10 and interferon-gamma regulation of experimental Trypanosoma cruzi infection. Journal of Experimental Medicine, 175, 169–174.

    Article  PubMed  CAS  Google Scholar 

  • Silva J.S., Vespa G.N.R., Cardoso M.A.G., Aliberti J.C.S., Cunha F.Q. 1995. Tumor necrosis factor alpha mediates resistance to Typanosoma cruzi infection in mice by inducing nitric oxide production in infected gamma interferon-activated macrophages. Infection and Immunity, 63, 4862–4867.

    PubMed  CAS  Google Scholar 

  • Soares M.B., Pontes-de-Carvalho L., Ribeiro-dos-Santos R. 2001. The pathogenesis of Chagas’ disease: when autoimmune and parasite-specific immune responses meet. Anais da Academia Brasileira de Ciências, 73, 547–559.

    PubMed  CAS  Google Scholar 

  • Solari A., Wallace A., Oritz S., Venegas J., Sanchez G. 2006. Biological characterization of Trypanosoma cruzi stocks from Chilean insect vectors. Experimental Parasitology, 89, 312–322.

    Article  Google Scholar 

  • Souto R.P., Fernandes O., Macedo A.M., Campbell D.A., Zingales B. 1996. DNA markers define two major phylogenetic lineages of Trypanosoma cruzi. Molecular and Biochemical Parasitology, 83, 141–152.

    Article  PubMed  CAS  Google Scholar 

  • Souza E.M. de, Araujo Jorge T.C., Bailly C., Lansiaux A., Batista M.M., Oliveira G.M., Soeiro M.N. 2003. Host and parasite apoptosis following Trypanosoma cruzi infection in vitro and in vivo models. Cell and Tissue Research, 314, 223–235.

    Article  PubMed  Google Scholar 

  • Souza M.M de., Andrade S.G., Barbosa A.A.Jr., Macedo Santos R.T., Ferreira Alves V.A., Andrade Z.A. 1996. Trypanosoma cruzi strains and autonomic nervous system pathology in experimental Chagas disease. Memorias do Instituto Oswaldo Cruz, 91, 217–224.

    PubMed  Google Scholar 

  • Storino R., Auger S., Caravello O., Urrutia M.I., Sanmartino M., Jorg M. 2002. Chagasic cardiopathy in endemic area versus sporadically infected patients. Revista da Saúde Pública, 36, 755–758 (In Spanish).

    Google Scholar 

  • Storino R., Milei J. 1986. Miocardiopatia Chagasica Cronica. Un Enfoque para el Clinico General. Club de Estudio, Buenos Aires.

  • Stothard J., Frame I., Miles M. 1999. Genetic diversity and genetic exchange in Trypanosoma cruzi: dual drug-resistant “progeny” from episomal transformants. Memorias do Instituto Oswaldo Cruz, 94,Suppl. 1, 189–193.

    PubMed  Google Scholar 

  • Talvani A., Ribeiro C.S., Aliberti J.C., Michailowsky V., Santos P.V., Murta S.M., Romanha A.J., Almeida I.C., Farber J., Lannes-Vieira J., Silva J.S., Gazzinelli R.T. 2000. Kinetics of cytokine gene expression in experimental chagasic cardiomyopathy: tissue parasitism and endogenous IFN-gamma as important determinants of chemokine mRNA expression during infection with Trypanosoma cruzi. Microbes and Infection, 2, 851–866.

    Article  PubMed  CAS  Google Scholar 

  • Talvani A., Rocha M.O., Barcelos M.S., Gomes Y.M., Ribeiro A.L., Teixeira M.M. 2004. Elevated concentrations of CCL2 and tumor necrosis factor-alpha in chagasic cardiomyopathy. Clinical Infectious Diseases, 38, 943–950.

    Article  PubMed  CAS  Google Scholar 

  • Tanowitz H.B., Huang H., Jelicks L.A., Chra M., Loredo M.L., Weiss L.M., Factor S.M., Shtutin V., Mukherjee S., Kitsis R.N., Christ G.J., Wittner M., Shirani J., Kisanuki Y.Y., Yanagisawa M. 2005. Role of endothelin 1 in the pathogenesis of chronic chagasic heart disease. Infection and Immunity, 73, 2496–2503.

    Article  PubMed  CAS  Google Scholar 

  • Tanowitz H.B., Kaul D.K., Chen B., Morris S.A., Factor S.M., Weiss L.M., Wittner M. 1996. Compromised microcirculation in acute murine Trypanosoma cruzi infection. Journal of Parasitology, 82, 124–130.

    Article  PubMed  CAS  Google Scholar 

  • Tanowitz H.B., Wittner M., Morris S.A., Zhao W., Weiss L.M., Hatcher V.B., Braunstein V.L., Huang H., Douglas S.A., Valcic M., Spektor M., Christ G.J. 1999. The putative mechanistic basis for the modulatory role of endothelin-1 in the altered vascular tone induced by Trypanosoma cruzi. Endothelium, 6, 217–230.

    PubMed  CAS  Google Scholar 

  • Tarleton R.L. 1991. The role of T-cell subpopulations in experimental Chagas’ disease. Research in Immunology, 142, 125–181.

    Article  Google Scholar 

  • Tarleton R.L. 1995. The role of T cells in Trypanosoma cruzi infections. Parasitology Today, 11, 7–9.

    Article  PubMed  CAS  Google Scholar 

  • Tibayrenc M. 2003. Genetic subdivisions within Trypanosoma cruzi (Discrete Typing Units) and their relevance for molecular epidemiology and experimental evolution. Kinetoplastid Biology and Disease, 2, 12.

    Article  PubMed  Google Scholar 

  • Torres S.H., Finol H.J., Montes de Oca M., Vasquez T., Puigbo J.J., Loyo J.G. 2004. Capillary damage in skeletal muscle in advanced Chagas’ disease patients. Parasitology Research, 93, 364–368.

    Article  PubMed  Google Scholar 

  • Torrico F., Heremans H., Rivera M.T., Marck E. van, Billiau A., Carlier Y. 1991. Endogenous IFN-gamma is required for resistance to acute Trypanosoma cruzi infection in mice. Journal of Immunology, 146, 3626–3632.

    CAS  Google Scholar 

  • Tostes S.Jr., Bertulucci Rocha-Rodrigues D., Araujo Pereira G. de, Rodrigues V.Jr. 2005. Myocardiocyte apoptosis in heart failure in chronic Chagas’ disease. International Journal of Cardiology, 99, 233–237.

    Article  PubMed  Google Scholar 

  • Vago A.R., Andrade L.O., Leite A.A., d’Avila Reis D., Macedo A.M., Adad S.J., Tostes S.Jr., Moreira M.C., Filho G.B., Pena S.D. 2000. Genetic characterization of Trypanosoma cruzi directly from tissues of patients with chronic Chagas disease: differential distribution of genetic types into diverse organs. American Journal of Pathology, 156, 1805–1809.

    PubMed  CAS  Google Scholar 

  • Vanderheyden M., Goethals M., Verstreken S., Bruyne B. de, Muller K., Schuerbeeck E. van, Bartunek J. 2004. Wall stress modulates brain natriuretic peptide production in pressure overload cardiomyopathy. Journal of the American College of Cardiology, 44, 2349–2354.

    Article  PubMed  CAS  Google Scholar 

  • Villalta F., Kierszenbaum F. 1984a. Role of inflammatory cells in Chagas’ disease. I. Uptake and mechanism of destruction of intracellular (amastigote) forms of Trypanosoma cruzi by human eosinophils. Journal of Immunology, 132, 2053–2058.

    CAS  Google Scholar 

  • Villalta F., Kierszenbaum F. 1984b. Role of inflammatory cells in Chagas’ disease. II. Interactions of mouse macrophages and human monocytes with intracellular forms of Trypanosoma cruzi: uptake and mechanism of destruction. Journal of Immunology, 133, 3338–3343.

    CAS  Google Scholar 

  • Villalta F., Kierszenbaum F. 1986. Effects of human colony-stimulating factor on the uptake and destruction of a pathogenic parasite (Trypanosoma cruzi) by human neutrophils. Journal of Immunology, 137, 1703–1707.

    CAS  Google Scholar 

  • Villalta F., Pankratz H.S., Kierszenbaum F. 1987. Extracellular killing of Trypanosoma cruzi amastigotes by human eosinophils. Journal of Protozoology, 34, 285–290.

    PubMed  CAS  Google Scholar 

  • Vyatkina G., Bhatia V., Gerstner A., Papaconstantinou J., Garg N. 2004. Impaired mitochondrial respiratory chain and bioenergetics during chagasic cardiomyopathy development. Biochimica et Biophysica Acta, 1689, 162–173.

    PubMed  CAS  Google Scholar 

  • Wallace D.C. 2000. Mitochondrial defects in cardiomyopathy and neuromuscular disease. American Heart Journal, 139, S70–S85.

    Article  PubMed  CAS  Google Scholar 

  • Wen J.J., Vyatkina G., Garg N. 2004. Oxidative damage during chagasic cardiomyopathy development: role of mitochondrial oxidant release and inefficient antioxidant defense. Free Radical Biology and Medicine, 37, 1821–1833.

    Article  PubMed  CAS  Google Scholar 

  • WHO (World Health Organization). 2002. Control of Chagas’ disease. Technical Report Series, WHO Publications, Geneva.

    Google Scholar 

  • Williams-Blangero S., VandeBerg J.L., Blangero J., Correa-Oliveira R. 2003. Genetic epidemiology of Trypanosoma cruzi infection and Chagas’ disease. Frontiers in Bioscience, 8, e337–e345.

    Article  PubMed  Google Scholar 

  • Witthaut R. 2004. Science review: natriuretic peptides in critical illness. Critical Care, London, 8, 342–349.

    Article  Google Scholar 

  • Zacks M.A., Wen J.J., Vyatkina G., Bhatia V., Garg N. 2005. An overview of chagasic cardiomyopathy: pathogenic importance of the oxidative stress. Anais da Academia Brasileira de Ciências, 77, 695–715.

    PubMed  CAS  Google Scholar 

  • Zhang J., Andrade Z.A., Yu Z.X. 1999. Apoptosis in a canine model of acute chagasic myocarditis. Journal of Molecular and Cellular Cardiology, 31, 581–596.

    Article  PubMed  CAS  Google Scholar 

  • Zhang L., Tarleton R.L. 1996. Persistent production of inflammatory and anti-inflammatory cytokines and associated MHC and adhesion molecule expression at the site of infection and disease in experimental Trypanosoma cruzi infections. Experimental Parasitology, 84, 203–213.

    Article  PubMed  CAS  Google Scholar 

  • Zingales B., Souto R.P., Mangia R., Lisboa C.V., Campbell D.A., Jansen A., Fernandes O. 1998. Molecular epidemiology of American trypanosomiasis in Brazil based on dimorphisms of rRNA and mini-exon gene sequences. International Journal for Parasitology, 28, 105–112.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Felipe Kierszenbaum.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kierszenbaum, F. Mechanisms of pathogenesis in Chagas disease. Acta Parasit. 52, 1–12 (2007). https://doi.org/10.2478/s11686-006-0048-y

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11686-006-0048-y

Key words

Navigation