The protozoan hemoflagellate Trypanosoma cruzi (T. cruzi) is the etiologic agent of the zoonotic Chagas’ disease that affects approximately six to seven million people in Central and South America, causing dilated cardiomyopathy and megavisceral disease. Although Chagas’ disease is the leading cause of heart failure in Latin America among people living in poverty and places an immense socioeconomic burden on society, it is still currently classified as a neglected tropical disease (NTD). The disease is typically transmitted by reduviid bugs or orally by contaminated food, while the transmission of parasitic organisms by other routes such as blood transfusion, organ transplantation, and transplacental infection is relatively rare. Given the wide cellular tropism infecting virtually all nucleated cells, the protozoan is able to persist asymptomatically for decades until ultimately causing organ-specific symptoms of chronic Chagas’ disease such as chronic heart failure. The acute phase of the disease triggers an immune response that often does not restrict the dissemination of the parasite and may cause skin lesions, fever, enlarged lymph nodes, pallor, swelling, and abdominal and chest pain. Despite recent advances in our knowledge about the pathogenesis of this disease, the complex host-parasite interactions are not completely understood and, in particular, the persistence of parasites in host cells for such a long time remains largely undefined. In this book chapter, we focus on the pathophysiology of American trypanosomiasis and emphasize the role of host-specific transcription factors executing antiparasitic immune reactions.
- Trypanosoma cruzi
- Chagas’ disease
- dilated cardiomyopathy
- immune response
- STAT transcription factors
The pathogenic protozoan
Chagas’ disease, also termed American trypanosomiasis, causes the third largest disease burden of the tropics after malaria and schistosomiasis  and is responsible for higher morbidity and mortality than any other parasitic infection in America . According to surveys of the World Health Organization (WHO) from 2014, six to seven million people worldwide are estimated to be infected with
The link between poverty and dissemination of Chagas’ disease is striking, as it particularly affects people living in simple huts made of mud and wood with roofs of straw or palm leaves in rural areas of Latin America, where the predatory bugs have easy access. In the most important endemic areas, vectors include
2. Biology and life cycle of
Assassin bugs infected with
Following a decline in incidence in endemic countries of Latin America, recorded in the mid-1990s up to the beginning of this millennium due to vector-eradication campaigns, Chagas’ disease is currently worldwide on the rise again even in Europe [15–21]. Alternative transmission modes of Chagas’ disease, such as congenital infection and infection through contaminated blood and organ donations, now play a major role both in classical endemic areas and in countries outside Latin America due to an increase in worldwide migration. The disease is, therefore, increasingly being detected in Europe, since more than 14 million people have left the endemic areas of South America, four to five million for Europe . In a statement from the WHO for Chagas’ disease in Europe in 2010, the number of
Chagas’ disease can also pose a threat to Germany. The data collection among the approximately 85,000 immigrants coming from endemic areas is, however, incomplete. It is estimated that the prevalence of seropositive immigrants is 1.3–1.7% (1100–1450-infected individuals); however, it is assumed that the number of patients is significantly underdiagnosed with Chagas’ disease [18, 24]. Epidemiological data from the United States of America estimated up to a million people infected with
4. Symptomatology of Chagas’ disease
Inflammatory lesions or nodules on the puncture wound in the face are less frequently observed manifestations of the acute stage (Chagoma), indicating a local inflammatory response with tissue destruction. Invasion of neutrophils and activation of tissue macrophages result in the secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). After a further 1–2 weeks, the stage of hematogenous and lymphatic spread is achieved, and further clinical symptoms of the acute phase may develop such as fever, anemia, muscle and bone pain, fatigue, diarrhea, lymphadenopathy, and hepatosplenomegaly. Whereas these symptoms typically disappear after 3–4 months, a small number of individuals, especially children, die from complications such as myocarditis or meningoencephalitis. The fatal course is highly dependent on the immune system and nutritional status of the host as well as the parasite load during transmission. The subsequent indeterminate phase is characterized by a very low parasitemia in the blood and can last for decades. Cellular immunity is at this stage an important endogenous strategy of the host to keep the parasites under control. Usually, 20–30% of seropositive patients develop the chronic phase of Chagas’ disease . In 40–50% of the affected patients, a progressive cardiomyopathy and less frequently neuronal dysfunction of the autonomic nerves of the gastrointestinal tract can develop . These symptoms are often found clinically only at a later stage, as many patients are initially asymptomatic. During routine analysis, radiological signs of left heart failure and cardiomegaly can be found. Damage to the heart may result in atrioventricular (AV), His-bundle or intraventricular blocks with Adam-Stokes seizures and syncopes . Cellular hypertrophy and subsequent chamber enlargement lead to systolic heart failure and may result in arrhythmias. Patients often die of sudden cardiac death induced by ventricular tachycardia and congestive heart failure . Histopathologic examination of endomyocardial biopsies shows myocardial fibrosis, resulting from cell lysis by trypanosomes and/or immune-pathological mechanisms. Development of gastrointestinal mega-syndrome, particularly the esophagus and colon, are additional clinical manifestations of chronic Chagas’ disease. The formation of mega-organs results from the destruction of the parasympathetic ganglia of the Meissner and Auerbach plexus in the gastrointestinal tract, which critically impairs peristalsis and leads to the ballooning of the organs. Clinically, these patients show symptoms of dysphagia, regurgitation, constipation, and secondary achalasia resulting from the dysfunction of the lower esophageal sphincter.
5. Diagnosis and treatment
Based on the aforementioned clinical signs of
In principle, two drugs for the treatment of acute Chagas’ disease are available, nifurtimox and benznidazole, which require prolonged treatment and may cause significant side effects . Nifurtimox, a nitrofuran with antiparasitic activity against both life cycle stages in the host, causes the accumulation of free radicals and superoxides and is generally genotoxic . The nitroimidazole derivate benznidazole is an antiparasitic medication equally effective against the two life-cycle stages. This drug inhibits the synthesis of RNA and generates the accumulation of superoxides . Although the parasite burden can be reduced below the detection limit in about 70% of all pharmacologically treated cases in acute Chagas’ disease, there is still no evidence that antiparasitic treatment can cure the patient completely from
Hitherto, the only sure prevention of the disease is the exposure prophylaxis by aerial spraying of insecticides and by modernization of traditional huts in rural areas.
7. Innate immune response to infections with
The innate immune system is essential in order to control the spread of
Activation of these pathways is critical for resistance to infection with
8. Apoptosis of cardiac myocytes in Chagas’ disease
The chronic stage of Chagas’ disease usually leads to symptoms of dilated cardiomyopathy, which is characterized by an enlargement of the heart muscle with a steadily progressive loss of systolic function. The decrease in the biventricular ejection volume is presumably reflecting altered heart muscle remodeling and may include apoptotic cell death. Apoptosis is a form of programmed cell death which differs from necrosis by actively carrying out a cell-death program . Apoptosis-regulating genes such as Bax and Apaf-1 are involved in the execution of apoptosis, whereas Bcl-2 is an antiapoptotic protein.
Proteolytic enzymes termed caspases play a central role in the execution of apoptotic cell death. The activation of the caspase cascade can be initiated by both intra- and extracellular stimuli. Extracellular stimuli induce the activation of caspases 8 and 10 through the Fas ligand and TNF receptors, whereas the intracellular pathway consists of the cytochrome C-regulated apoptosome which activates caspase 9. The JAK-STAT-signaling pathway regulates apoptosis via STAT3 (signal transducer and activator of transcription 3) by promoting the expression of antiapoptotic genes coding for the Bcl-2 protein family . Cytotoxic T lymphocytes (CTLs, CD8+ T-cells) activate caspases 3 and 7. These are key caspases in which caspases 8 and 9 converge and henceforth result in a common final pathway of the signaling cascade. Apoptosis of cardiomyocytes in the context of
In autopsy samples from Chagas’ cardiomyopathy patients, signs of apoptotic cell death were detected post mortem in cardiac myocytes , confirming earlier results that
However, there are conflicting results on the role of apoptosis in murine cardiomyocytes during infection with
The JAK-STAT-signaling pathway has an important role in cardiomyopathy, myocarditis, and myocardial infarction . Cardiomyocytes express various receptors for cytokines and growth factors (among others, TNFα and EGF) on their surface. Secreted cytokines or growth factors may be involved in the apoptotic cell death of cardiomyocytes and chronic cardiomyopathy. Specifically, the balance in the activation state of the two related transcription factors STAT1 and STAT3 may determine the outcome between cell death and survival of cardiac muscle cells during infection with
In the context of chronic Chagas’ disease, which can develop up to 25 years after parasitic infection, the question arises as to how the parasite can persist and replicate for such a long period of time in the host without causing an exacerbating immune response. The most obvious explanation is that the parasite has developed effective mechanisms to circumvent the immune response which affects the steady balance between parasite load and apoptosis-induced destruction of host cells. Various parasitological studies highlight the dogma that the replication of parasites in the cardiac myocytes is required to initiate the complete picture of Chagas’ heart disease ranging from acute myocarditis to chronic cardiomyopathy .
9. The role of STAT proteins in Chagas’ cardiomyopathy
There is growing evidence that not only NF-kB but also STAT transcription factors are engaged in
In addition, Ponce et al. demonstrated that, in
Previous studies have described how STAT3 is activated by the two cytokines IL-6 or IL-10 [91, 92] and how the expression of SOCS3 is upregulated by the anti-inflammatory IL-10 in
Another member of the STAT family, the transcription factor STAT4, is activated in response to the cytokine IL-12, which acts as a pro-inflammatory cytokine and drives Th cells along a Th1 lineage. STAT6 is activated by receptor binding of two cytokines with anti-inflammatory properties, IL-4 and IL-13, which provide an alternative signal for the development along a Th2 lineage. Tarleton and coworkers demonstrated that STAT4-deficient mice were highly susceptible to infection with
10. Concluding remarks
In summary, the pathogenic protozoan
The research on this subject was funded by grants from Deutsche Forschungsgemeinschaft (DFG), Deutsche Gesellschaft für Kardiologie (DGK), and Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK).
Chagas C. Nova tripanozomiase humana. Estudos sobre a morfologia e o ciclo evolutivo do Schizotrypanum cruzi n. gen., n. sp., agente etiológico de nova entidade mórbida do homem. Mem. Inst. Oswaldo Cruz 1909; 1:159–218.
Moncayo A. Progress towards the elimination of transmission of Chagas disease in Latin America. World Health Stat. Q. 1997; 50:195–198.
Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet 2010; 375:1388–1402.
Schaub GA. Pathogenicity of trypanosomatids on insects. Parasitol. Today 1994; 10:463–468.
Sánchez LV, Ramírez JD. Congenital and oral transmission of American trypanosomiasis: an overview of physiopathogenic aspects. Parasitology 2013; 140:147–159.
Brener Z. Biology of Trypanosoma cruzi. Annu. Rev. Microbiol. 1973; 27:347–382.
Vickerman K. Developmental cycles and biology of pathogenic trypanosomes. Br. Med. Bull. 1985: 41:105–114.
De Souza W. Basic cell biology of Trypanosoma cruzi. Curr. Pharm. Des. 2002; 8:269–285.
Andrews NW. Living dangerously: how Trypanosoma cruziuses lysosomes to get inside host cells, and then escapes into the cytoplasm. Biol. Res. 1993: 26:65–67.
Tan H, Andrews NW. Don’t bother to knock—the cell invasion strategy of Trypanosoma cruzi. Trends Parasitol. 2002; 18:427–428.
Burleigh BA, Andrews NW. The mechanisms of Trypanosoma cruziinvasion of mammalian cells. Annu. Rev. Microbiol. 1995; 49:175–200.
Tyler KM, Engman DM. The life cycle of Trypanosoma cruzirevisited. Int. J. Parasitol. 2001; 31:472–481.
Ferreira ER, Bonfim-Melo A, Mortara RA, Bahia D. Trypanosoma cruziextracellular amastigotes and host cell signaling: more pieces to the puzzle. Front. Immunol. 2012; 3:363.
De Souza W. Cell biology of Trypanosoma cruzi. Int. Rev. Cytol. 1984; 86:197–283.
Schofield CJ, Dias JC. The Southern Cone Initiative against Chagas disease. Adv. Parasitol. 1999; 42:1–27.
Moncayo A, Silveira AC. Current epidemiological trends for Chagas disease in Latin America and future challenges in epidemiology, surveillance and health policy. Mem. Inst. Oswaldo Cruz 104 Suppl 2009; 1:17–30.
Gascon J, Bern C, Pinazo MJ. Chagas disease in Spain, the United States and other non-endemic countries. Acta Trop. 2010; 115:22–27.
Basile L, Jansá JM, Carlier Y, Salamanca DD, Angheben A, Bartoloni A, Seixas J, Van Gool T, Canavate C, Flores-Chávez M, Jackson Y, Chiodini PL, Albajar-Vinas P, and Working Group on Chagas Disease. Chagas disease in European countries: the challenge of a surveillance system. Euro. Surveill. 2011; 16.
Angheben A, Anselmi M, Gobbi F, Marocco S, Monteiro G, Buonfrate D, Tais S, Talamo M, Zavarise G, Strohmeyer M, Bartalesi F, Mantella A, Di Tommaso M, Aiello KH, Veneruso G, Graziani G, Ferrari M, Spreafico I, Bonifacio E, Gaiera G, Lanzafame M, Mascarello M, Cancrini G, Albajar-Vinas P, Bisoffi Z, Bartoloni A. Chagas disease in Italy: breaking an epidemiological silence. Euro. Surveill. 2011: 16.
Perez-Molina JA, Perez-Ayala A, Parola P, Jackson Y, Odolini S, Lopez-Velez R, and EuroTravNet Network. EuroTravNet: imported Chagas disease in nine European countries, 2008 to 2009. Euro Surveill. Bull. 2011; 16.
Albajar-Vinas P, Jannin J. The hidden Chagas disease burden in Europe. Euro Surveill. 2011; 16*.
Schmunis GA, Yadon ZE. Chagas disease: a Latin American health problem becoming a world health problem. Acta Trop. 2010; 115:14–21.
Jackson Y, Chappuis F. Chagas disease in Switzerland: history and challenges. Euro. Surveill. 2011; 16.
Strasen J, Williams T, Ertl G, Zoller T, Stich A, Ritter O. Epidemiology of Chagas disease in Europe: many calculations, little knowledge. Clin. Res. Cardiol. 2014; 103:1–10.
Hotez PJ, Dumonteil E, Betancourt Cravioto M, Bottazzi ME, Tapia-Conyer R, Meymandi S, Karunakara U, Ribeiro I, Cohen RM, Pecoul B. An unfolding tragedy of Chagas disease in North America. PLoS Negl. Trop. Dis. 2013; 7:e2300.
Salas Clavijo NA, Postigo JR, Schneider D, Santalla JA, Brutus L, Chippaux JP. Prevalence of Chagas disease in pregnant women and incidence of congenital transmission in Santa Cruz de la Sierra, Bolivia. Acta Trop. 2012; 124:87–91.
Jackson Y, Pinto A, Pett S. Chagas disease in Australia and New Zealand: risks and needs for public health interventions. Trop. Med. Int. Health 2014, 19:212–218.
Rossi MA, Bestetti RB. The challenge of chagasic cardiomyopathy. The pathologic roles of autonomic abnormalities, autoimmune mechanisms and microvascular changes, and therapeutic implications. Cardiology 1995; 86:1–7.
Rassi A Jr, Rassi A, Marcondes de Rezende J. American Trypanosomiasis (Chagas Disease). Infect. Dis. Clin. North Am. 2012; 26:275–291.
Marin-Neto JA, Cunha-Neto E, Maciel BC, Simões MV. Pathogenesis of chronic Chagas heart disease. Circulation 2007; 115:1109–1123.
de Lourdes Higuchi M, Benvenuti LA, Martins Reis M, Metzger M. Pathophysiology of the heart in Chagas’ disease: current status and new developments. Cardiovasc. Res. 2003; 60:96–107.
Otani MM, Vinelli E, Kirchhoff LV, del Pozo A, Sands A, Vercauteren G, Sabino EC. WHO comparative evaluation of serologic assays for Chagas disease. Transfusion (Paris) 2009; 49:1076–1082.
Brumpt E. Le xenodiagnostic. Application au diagnostic de quelques infections parasitaires et en particulier à la trypanosome de Chagas. Bull. Soc. Path. Exot. 1914; 77:706–710.
Lattes R, Lasala MB. Chagas disease in the immunosuppressed patient. Clin. Microbiol. Infect. 2014; 20:300–309.
Le Loup G, Pialoux G, Lescure FX. Update in treatment of Chagas disease. Curr. Opin. Infect. Dis. 2011; 24:428–434.
Marin-Neto JA, Rassi A, Avezum A, Mattos AC, Rassi A, Morillo CA, Sosa-Estani S, Yusuf S, and BENEFIT Investigators. The BENEFIT trial: testing the hypothesis that trypanocidal therapy is beneficial for patients with chronic Chagas heart disease. Mem. Inst. Oswaldo Cruz 104 Suppl 2009; 1:319–324.
Apt W. Current and developing therapeutic agents in the treatment of Chagas disease. Drug Des. Devel. Ther. 2010; 4:243–253.
Bern C. Chagas’ Disease. N. Engl. J. Med. 2015; 373:456–466.
Garcia S, Ramos CO, Senra JFV, Vilas-Boas F, Rodrigues MM, Campos-de-Carvalho AC, Ribeiro-dos-Santos R, Soares MBP. Treatment with benznidazole during the chronic phase of experimental Chagas’ disease decreases cardiac alterations. Antimicrob. Agents Chemother. 2005; 49:1521–1528.
Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez MG, Postan M, Armenti A. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann. Intern. Med. 2006: 144:724–734.
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, and BENEFIT Investigators. Randomized trial of benznidazole for chronic Chagas' cardiomyopathy. N. Engl. J. Med. 2015; 373:1295–1306.
Debierre-Grockiego F. Glycolipids are potential targets for protozoan parasite diseases. Trends Parasitol. 2010; 26:404–411.
Schauer R, Kamerling JP. The chemistry and biology of trypanosomal trans-sialidases: virulence factors in Chagas disease and sleeping sickness. ChemBioChem 2011; 12:2246–2264.
Machado FS, Dutra WO, Esper L, Gollob KJ, Teixeira MM, Factor SM, Weiss LM, Nagajyothi F, Tanowitz HB, Garg NJ. Current understanding of immunity to Trypanosoma cruziinfection and pathogenesis of Chagas disease. Semin. Immunopathol. 2012; 34:753–770.
Takeda K, Akira S. Toll-like receptors in innate immunity. Int. Immunol. 2005; 17:1–14.
Campos MA, Almeida IC, Takeuchi O, Akira S, Valente EP, Procópio DO, Travassos LR, Smith JA, Golenbock DT, Gazzinelli RT. Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J. Immunol. 2001; 167:416–423.
Ropert C, Gazzinelli RT. Regulatory role of Toll-like receptor 2 during infection with Trypanosoma cruzi. J. Endotoxin Res. 2004; 10:425–430.
Oliveira AC, Peixoto JR, de Arruda LB, Campos MA, Gazzinelli RT, Golenbock DT, Akira S, Previato JO, Mendonça-Previato L, Nobrega A, Bellio M. Expression of functional TLR4 confers proinflammatory responsiveness to Trypanosoma cruziglycoinositolphospholipids and higher resistance to infection with T. cruzi. J. Immunol. 2004; 173:5688–5696.
Bafica A, Santiago HC, Goldszmid R, Ropert C, Gazzinelli RT, Sher A. Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruziinfection. J. Immunol. 2006; 177:3515–3519.
Medeiros MM, Peixoto JR, Oliveira AC, Cardilo-Reis L, Koatz VLG, Van Kaer L, Previato JO, Mendonça-Previato L, Nobrega A, Bellio M. Toll-like receptor 4 (TLR4)-dependent proinflammatory and immunomodulatory properties of the glycoinositolphospholipid (GIPL) from Trypanosoma cruzi. J. Leukoc. Biol. 2007; 82:488–496.
Caetano BC, Carmo BB, Melo MB, Cerny A, dos Santos SL, Bartholomeu DC, Golenbock DT, Gazzinelli RT. Requirement of UNC93B1 reveals a critical role for TLR7 in host resistance to primary infection with Trypanosoma cruzi. J. Immunol. 2011; 187:1903–1911.
Gravina HD, Antonelli L, Gazzinelli RT, Ropert C. Differential use of TLR2 and TLR9 in the regulation of immune responses during the infection with Trypanosoma cruzi. PloS One 2013; 8:e63100.
Heidecker B, Kittleson MM, Kasper EK, Wittstein IS, Champion HC, Russell SD, Hruban RH, Rodriguez ER, Baughman KL, Hare JM. Transcriptomic biomarkers for the accurate diagnosis of myocarditis. Circulation 2011; 123:1174–1184.
Gonçalves VM, Matteucci KC, Buzzo CL, Miollo BH, Ferrante D, Torrecilhas AC, Rodrigues MM, Alvarez JM, Bortoluci KR. NLRP3 controls Trypanosoma cruziinfection through a caspase-1-dependent IL-1R-independent NO production. PLoS Negl. Trop. Dis. 2013; 7:e2469.
Truyens C, Angelo-Barrios A, Torrico F, Van Damme J, Heremans H, Carlier Y. Interleukin-6 (IL-6) production in mice infected with Trypanosoma cruzi: effect of its paradoxical increase by anti-IL-6 monoclonal antibody treatment on infection and acute-phase and humoral immune responses. Infect. Immun. 1994: 62:692–696.
Aliberti JC, Cardoso MA, Martins GA, Gazzinelli RT, Vieira LQ, Silva, JS. Interleukin-12 mediates resistance to Trypanosoma cruziin mice and is produced by murine macrophages in response to live trypomastigotes. Infect. Immun. 1996; 64:1961–1967.
Camargo MM, Almeida IC, Pereira ME, Ferguson MA, Travassos LR, Gazzinelli RT. Glycosylphosphatidylinositol-anchored mucin-like glycoproteins isolated from Trypanosoma cruzitrypomastigotes initiate the synthesis of proinflammatory cytokines by macrophages. J. Immunol. 1997; 158:5890–5901.
Almeida IC, Camargo MM, Procópio DO, Silva LS, Mehlert A, Travassos LR, Gazzinelli RT, Ferguson MA. Highly purified glycosylphosphatidylinositols from Trypanosoma cruziare potent proinflammatory agents. EMBO J. 2000; 19:1476–1485.
Antúnez MI, Cardoni RL. IL-12 and IFN-γ production, and NK cell activity, in acute and chronic experimental Trypanosoma cruziinfections. Immunol. Lett. 2000; 71:103–109.
Michailowsky V, Silva NM, Rocha CD, Vieira LQ, Lannes-Vieira J, Gazzinelli RT. Pivotal role of interleukin-12 and interferon-gamma axis in controlling tissue parasitism and inflammation in the heart and central nervous system during Trypanosoma cruziinfection. Am. J. Pathol. 2001; 159:1723–1733.
Bastos KRB, Barboza R, Sardinha L, Russo M, Alvarez JM, Lima MRD. Role of endogenous IFN-γ in macrophage programming induced by IL-12 and IL-18. J. Interferon Cytokine Res. 2007; 27:399–410.
Kierszenbaum F, Sonnenfeld G. Beta-interferon inhibits cell infection by Trypanosoma cruzi. J. Immunol. 1984; 132:905–908.
Koga R, Hamano S, Kuwata H, Atarashi K, Ogawa M, Hisaeda H, Yamamoto M, Akira S, Himeno K, Matsumoto M, Takeda K. TLR-dependent induction of IFN-β mediates host defense against Trypanosoma cruzi. J. Immunol. 2006; 177:7059–7066.
Chessler ADC, Ferreira LRP, Chang TH, Fitzgerald KA, Burleigh BA. A novel IFN regulatory factor 3-dependent pathway activated by trypanosomes triggers IFN-β in macrophages and fibroblasts. J. Immunol. 2008; 181:7917–7924.
Wirth JJ, Kierszenbaum F, Sonnenfeld G, Zlotnik A. Enhancing effects of gamma interferon on phagocytic cell association with and killing of Trypanosoma cruzi. Infect. Immun. 1985: 49:61–66.
Müller U, Köhler G, Mossmann H, Schaub GA, Alber G, Di Santo JP, Brombacher F, Hölscher C. IL-12-independent IFN-γ production by T cells in experimental Chagas’ disease is mediated by IL-18. J. Immunol. 2001; 167:3346–3353.
Rodrigues AA, Saosa JSS, da Silva GK, Martins FA, da Silva AA, da Silva Souza Neto CP, Horta CV, Zamboni DS, da Silva JS, Ferro EAV, da Silva CV. IFN-γ plays a unique role in protection against low virulent Trypanosoma cruzistrain. PLoS Negl. Trop. Dis. 2012; 6:e1598.
Campos MA, Closel M, Valente EP, Cardoso JE, Akira S, Alvarez-Leite JI, Ropert C, Gazzinelli RT. Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruziin mice lacking functional myeloid differentiation factor 88. J. Immunol. 2004; 172:1711–1718.
Huang H, Calderon TM, Berman JW, Braunstein VL, Weiss LM, Wittner M, Tanowitz HB. Infection of endothelial cells with Trypanosoma cruziactivates NF-kappaB and induces vascular adhesion molecule expression. Infect. Immun. 1999; 67:5434–5440.
Hall BS, Tam W, Sen R, Pereira ME. Cell-specific activation of nuclear factor-kappaB by the parasite Trypanosoma cruzipromotes resistance to intracellular infection. Mol. Biol. Cell 2000; 11:153–160.
Hovsepian E, Penas F, Siffo S, Mirkin GA, Goren NB. IL-10 inhibits the NF-κB and ERK/MAPK-mediated production of pro-inflammatory mediators by up-regulation of SOCS-3 in Trypanosoma cruzi-infected cardiomyocytes. PloS One 2013; 8:e79445.
Hölscher C, Köhler G, Müller U, Mossmann H, Schaub GA, Brombacher F. Defective nitric oxide effector functions lead to extreme susceptibility of Trypanosoma cruzi-infected mice deficient in gamma-interferon receptor or inducible nitric oxide synthase. Infect. Immun. 1998; 66:1208–1215.
Böhm I, Schild H. Apoptosis: the complex scenario for a silent cell death. Mol. Imaging Biol. 2003; 5:2–14.
Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K, Hirano T. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity. 1996; 5:449–460.
Tostes S Jr, Bertulucci Rocha-Rodrigues D, de Araujo Pereira G, Rodrigues V Jr. Myocardiocyte apoptosis in heart failure in chronic Chagas’ disease. Int. J. Cardiol. 2005: 99:233–237.
Zhang J, Andrade ZA, Yu ZX, Andrade SG, Takeda K, Sadirgursky M, Ferrans VJ. Apoptosis in a canine model of acute Chagasic myocarditis. J. Mol. Cell. Cardiol. 1999; 31:581–596.
Henriques-Pons A, Oliveira GM, Paiva MM, Correa AFS, Batista MM, Bisaggio RC, Liu CC, Cotta-de-Almeida V, Coutinho CMLM, Persechini PM, Araújo-Jorge. Evidence for a perforin-mediated mechanism controlling cardiac inflammation in Trypanosoma cruziinfection. Int. J. Exp. Pathol. 2002; 83:67–79.
Manque PA, Probst CM, Probst CM, Pereira MCS, Rampazzo RCP, Ozaki LS, Ozaki LS, Pavoni DP, Silva Neto DT, Carvalho MR, Xu P, Serrano MG, Alves JMP, de Nazareth SL Meirelles M, Goldenberg S, Krieger MA, Buck GA. Trypanosoma cruziinfection induces a global host cell response in cardiomyocytes. Infect. Immun. 2011; 79:1855–1862.
De Souza EM, Araújo-Jorge TC, Bailly C, Lansiaux A, Batista MM, Oliveira GM, Soeiro MN. Host and parasite apoptosis following Trypanosoma cruziinfection in in vitro and in vivo models. Cell Tissue Res. 2003: 314:223–235.
Aoki MP, Guiñazú NL, Pellegrini AV, Gotoh T, Masih DT, Gea S. Cruzipain, a major Trypanosoma cruziantigen, promotes arginase-2 expression and survival of neonatal mouse cardiomyocytes. Am. J. Physiol. Cell Physiol. 2004; 286:C206–212.
Stahl P, Ruppert V, Meyer T, Schmidt J, Campos MA, Gazzinelli RT, Maisch B, Schwarz RT, Debierre-Grockiego F. Trypomastigotes and amastigotes of Trypanosoma cruziinduce apoptosis and STAT3 activation in cardiomyocytes in vitro. Apoptosis 2013; 18:653–663.
Petersen CA, Krumholz KA, Carmen J, Sinai AP, Burleigh BA. Trypanosoma cruziinfection and nuclear factor kappa B activation prevent apoptosis in cardiac cells. Infect. Immun. 2006; 74:1580–1587.
De Souza EM, Nefertiti ASG, Bailly C, Lansiaux A, Soeiro MN. Differential apoptosis-like cell death in amastigote and trypomastigote forms from Trypanosoma cruzi-infected heart cells in vitro. Cell Tissue Res. 2010; 341:173–180.
Barry SP, Townsend PA, Latchman DS, Stephanou A. Role of the JAK-STAT pathway in myocardial injury. Trends Mol. Med. 2007; 13:82–89.
Stahl P, Schwarz RT, Debierre-Grockiego F, Meyer T. Trypanosoma cruziparasites fight for control of the JAK-STAT pathway by disarming their host. JAK-STAT 2015; 3:e1012964.
Tarleton RL, Zhang L. Chagas disease etiology: autoimmunity or parasite persistence? Parasitol. Today 1999; 15:94–99.
Stahl P, Ruppert V, Schwarz RT, Meyer T. Trypanosoma cruzievades the protective role of interferon-gamma-signaling in parasite-infected cells. PLoS One 2014; 9:e110512.
Ponce NE, Cano RC, Carrera-Silva EA, Lima AP, Gea S, Aoki MP. Toll-like receptor-2 and interleukin-6 mediate cardiomyocyte protection from apoptosis during Trypanosoma cruzimurine infection. Med. Microbiol. Immunol. 2012; 201:145–155.
Ponce NE, Carrera-Silva EA, Pellegrini AV, Cazorla SI, Malchiodi EL, Lima AP, Gea S, Aoki MP. Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukin-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells. Biochim. Biophys. Acta 2013; 1832:485–494.
Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ. A family of cytokine-inducible inhibitors of signalling. Nature 1997; 387:917–921.
Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 1994; 264:95–98.
Riley JK, Takeda K, Akira S, Schreiber RD. Interleukin-10 receptor signaling through the JAK-STAT pathway. Requirement for two distinct receptor-derived signals for anti-inflammatory action. J. Biol. Chem. 1999; 274:16513–16521.
Esper L, Roman-Campos D, Lara A, Brant F, Castro LL, Barroso A, Araujo RRS, Vieira LQ, Mukherjee S, Gomes ERM, Rocha NN, Ramos IPR, Lisanti MP, Campos CF, Arantes RME Guatimosim S, Weiss LM, Cruz JS, Tanowitz HB, Teixeira MM, Machado FS. Role of SOCS2 in modulating heart damage and function in a murine model of acute Chagas disease. Am. J. Pathol. 2012; 181:130–140.
Tarleton RL, Grusby MJ, Zhang L. Increased susceptibility of Stat4-deficient and enhanced resistance in Stat6-deficient mice to infection with Trypanosoma cruzi. J. Immunol. 2000; 165:1520-1525.