Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 117 | 2022

Multi-therapeutic strategy targeting parasite and inflammation-related alterations to improve prognosis of chronic Chagas cardiomyopathy: a hypothesis-based approach*

Joseli Lannes-Vieira+

Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Biologia das Interações, Rio de Janeiro, RJ, Brasil

DOI: 10.1590/0074-02760220019
825 views 260 downloads

Chagas disease (CD), caused by infection by the protozoan parasite Trypanosoma cruzi, presents as main clinical manifestation the chronic chagasic cardiomyopathy (CCC). CCC afflicts millions of people, mostly in Latin America, and vaccine and effective therapy are still lacking. Comprehension of the host/parasite interplay in the chronic phase of T. cruzi infection may unveil targets for rational trait-based therapies to improve CCC prognosis. In the present viewpoint, I critically summarize a collection of data, obtained by our network of collaborators and other groups on CCC and preclinical studies on pathogenesis, targeting identification for intervention and the use of drugs with immunomodulatory properties to improve CCC. In the last two decades, models combining mouse lineages and T. cruzi strains allowed replication of crucial clinical, histopathological, and immunological traits of CCC. This condition includes conduction changes (heart rate changes, arrhythmias, atrioventricular blocks, prolongation of the QRS complex and PR and corrected QT intervals), ventricular dysfunction and heart failure, CD8-enriched myocarditis, tissue remodeling and progressive fibrosis, and systemic inflammatory profile, resembling “cytokine storm”. Studies on Chagas’ heart disease pathogenesis begins to unveil the molecular mechanisms underpinning the inflammation-related cardiac tissue damage, placing IFNγ, TNF and NFκB signaling as upstream regulators of miRNAs and mRNAs associated with critical biological pathways as cell migration, inflammation, tissue remodeling and fibrosis, and mitochondrial dysfunction. Further, data on preclinical trials using hypothesis-based tools, targeting parasite and inflammation-related alterations, opened paths for multi-therapeutic approaches in CCC. Despite the long path taken using experimental CD models replicating relevant aspects of CCC and testing new therapies and therapeutic schemes, these findings may get lost in translation, as conceptual and economical challenges, underpinning the valley of death across preclinical and clinical trials. It is hoped that such difficulties will be overcome in the near future.

01. Dias JC, Ramos Jr AN, Gontijo ED, Luquetti A, Shikanai-Yasuda MA, Coura JR, et. [Brazilian Consensus on Chagas Disease, 2015]. Epidemiol Serv Saude. 2016; 25(spe): 7-86.
02. Camargo EP, Gazzinelli RT, Morel CM, Precioso AR. Why do we still have not a vaccine against Chagas disease? Mem Inst Oswaldo Cruz. 2021; 116: e200314.
03. Saraiva RM, Meymandi S. Management of chronic chagasic cardiomyopathy in endemic and non-endemic countries: challenges and limitations. In Delgado MJP, Gascón J, editors. Chagas disease - a neglected tropical disease. Springer; 2020. p. 145.
04. Acevedo GR, Girard MC, Gómez KA. The unsolved jigsaw puzzle of the immune response in Chagas disease. Front Immunol. 2018; 9: 1929.
05. Dantas-Pereira L, Menna-Barreto R, Lannes-Vieira J. Extracellular vesicles: potential role in remote signaling and inflammation in Trypanosoma cruzi-triggered disease. Front Cell Dev Biol. 2021; 9: 798054.
06. Urbina JA. Etiologic treatment of Chagas cisease: old drugs, new insights, challenges, and perspectives. In Delgado MJP, Gascón J, editors. Chagas disease - a neglected tropical disease. Springer; 2020. p. 123.
07. Rassi Jr A, Marin-Neto JA, Rassi A. Chronic Chagas cardiomyopathy: a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the BENznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial. Mem Inst Oswaldo Cruz. 2017; 112(3): 224-35.
08. Bocchi EA, Bestetti RB, Scanavacca MI, Cunha Neto E, Issa VS. Chronic Chagas heart disease management: from etiology to cardiomyopathy treatment. J Am Coll Cardiol. 2017; 70(12): 1510-24.
09. Pérez-Fuentes R, Guégan JF, Barnabé C, López-Colombo A, Salgado- Rosas H, Torres-Rasgado E, et al. Severity of chronic Chagas disease is associated with cytokine/antioxidant imbalance in chronically infected individuals. Int J Parasitol. 2003; 33(3): 293-9.
10. Pérez AR, Silva-Barbosa SD, Berbert LR, Revelli S, Beloscar J, Savino W, et al. O Immunoneuroendocrine alterations in patients with progressive forms of chronic Chagas disease. J Neuroimmunol. 2011; 235(1-2): 84-90.
11. Neves EGA, Koh CC, Padilha da Silva JL, Passos LSA, Villani FNA, dos Santos JSC, et al. Systemic cytokines, chemokines and growth factors reveal specific and shared immunological characteristics in infectious cardiomyopathies. Cytokine. 2021; 148: 155711.
12. Pereira IR, Vilar-Pereira G, da Silva AA, Lannes-Vieira J. Severity of chronic experimental Chagas’ heart disease parallels tumour necrosis factor and nitric oxide levels in the serum: models of mild and severe disease. Mem Inst Oswaldo Cruz. 2014; 109(3): 289-98.
13. Daliry A, Pereira IR, Pereira-Junior PP, Ramos IP, Vilar-Pereira G, Silvares RR, et al. Levels of circulating anti-muscarinic and anti-adrenergic antibodies and their effect on cardiac arrhythmias and dysautonomia in murine models of Chagas disease. Parasitology. 2014; 141(13): 1769-78.
14. Silverio JC, Pereira IR, Cipitelli MC, Vinagre NF, Rodrigues MM, Gazzinelli RT, et al. CD8+ T-cells expressing interferon gamma or perforin play antagonistic roles in heart injury in experimental Trypanosoma cruzi-elicited cardiomyopathy. PLoS Pathog. 2012; 8(4): e1002645.
15. Pereira IR, Vilar-Pereira G, Marques V, da Silva AA, Caetano B, Moreira OC, et al. A human type 5 adenovirus-based Trypanosoma cruzi therapeutic vaccine re-programs immune response and reverses chronic cardiomyopathy. PLoS Pathog. 2015; 11(1): e1004594.
16. Kroll-Palhares K, Silvério JC, da Silva AA, Michailowsky V, Marino AP, Silva NM, et al. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-alpha blockade. Mem Inst Oswaldo Cruz. 2008; 103(4): 375-85.
17. Pereira IR, Vilar-Pereira G, Silva AA, Moreira OC, Britto C, Sarmento ED, et al. Tumor necrosis factor is a therapeutic target for immunological unbalance and cardiac abnormalities in chronic experimental Chagas’ heart disease. Mediators Inflamm. 2014; 2014: 798078.
18. Pereira IR, Vilar-Pereira G, Moreira OC, Ramos IP, Gibaldi D, Britto C, et al. Pentoxifylline reverses chronic experimental Chagasic cardiomyopathy in association with repositioning of abnormal CD8+ T-cell response. PLoS Negl Trop Dis. 2015; 9(3): e0003659.
19. Teixeira MM, Gazzinelli RT, Silva JS. Chemokines inflammation and Trypanosoma cruzi infection. Trends Parasitol. 2002; 18(6): 262-5.
20. Paiva CN, Medei E, Bozza MT. ROS and Trypanosoma cruzi: fuel to infection, poison to the heart. PLoS Pathog. 2018; 14(4): e1006928.
21. Wen JJ, Yachelini PC, Sembaj A, Manzur RE, Garg NJ. Increased oxidative stress is correlated with mitochondrial dysfunction in chagasic patients. Free Radic Biol Med. 2006; 41(2): 270-6.
22. Wen JJ, Garg NJ. Manganese superoxide dismutase deficiency exacerbates the mitochondrial ROS production and oxidative damage in Chagas disease. PLoS Negl Trop Dis. 2018; 12(7): e0006687.
23. Chevillard C, Nunes JPS, Frade AF, Almeida RR, Pandey RP, Nascimento MS, et al. Disease tolerance and pathogen resistance genes may underlie Trypanosoma cruzi persistence and differential progression to Chagas disease cardiomyopathy. Front Immunol. 2018; 9: 2791.
24. Freire-de-Lima CG, Nascimento DO, Soares MB, Bozza PT, Castro- Faria-Neto HC, de Mello FG, et al. Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature. 2000; 403(6766): 199-203.
25. Waghabi MC, Ferreira RR, Abreu RS, Degrave W, de Souza EM, Bailly S, et al. Transforming growth factor-β as a therapeutic target for the cardiac damage of Chagas disease. Mem Inst Oswaldo Cruz. 2022; 116: e210395.
26. Saraiva RM, Waghabi MC, Vilela MF, Madeira FS, Sperandio da Silva GM, Xavier SS, et al. Predictive value of transforming growth factor-β1in Chagas disease: towards a biomarker surrogate of clinical outcome. Trans R Soc Trop Med Hyg. 2013; 107(8): 518-25.
27. Ferreira RR, Abreu RDS, Vilar-Pereira G, Degrave W, Meuser- Batista M, Ferreira NVC, et al. TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas’ heart disease. PLoS Negl Trop Dis. 2019; 13(7): e0007602.
28. Reis DD, Jones EM, Tostes Jr S, Lopes ER, Gazzinelli G, Colley DG, et al. Characterization of inflammatory infiltrates in chronic chagasic myocardial lesions: presence of tumor necrosis factoralpha+ cells and dominance of granzyme A+, CD8+ lymphocytes. Am J Trop Med Hyg. 1993; 48(5): 637-44.
29. Medeiros GA, Silvério JC, Marino AP, Roffê E, Vieira V, Kroll- Palhares K, et al. Treatment of chronically Trypanosoma cruziinfected mice with a CCR1/CCR5 antagonist (Met-RANTES) results in amelioration of cardiac tissue damage. Microbes Infect. 2009; 11(2): 264-73.
30. Gibaldi D, Vilar-Pereira G, Pereira IR, Silva AA, Barrios LC, Ramos IP, et al. CCL3/macrophage inflammatory protein-1α is dually involved in parasite persistence and induction of a TNFand IFNγ-enriched inflammatory milieu in Trypanosoma cruziinduced chronic cardiomyopathy. Front Immunol. 2020; 11: 306.
31. Marino AP, da Silva A, dos Santos P, Pinto LM, Gazzinelli RT, Teixeira MM, et al. Regulated on activation, normal T cell expressed and secreted (RANTES) antagonist (Met-RANTES) controls the early phase of Trypanosoma cruzi-elicited myocarditis. Circulation. 2004; 110(11): 1443-9.
32. Batista AM, Alvarado-Arnez LE, Alves SM, Melo G, Pereira IR, Ruivo LAS, et al. Genetic polymorphism at CCL5 is associated with protection in Chagas’ heart disease: antagonistic participation of CCR1+ and CCR5+ cells in chronic chagasic cardiomyopathy. Front Immunol. 2018; 9: 615.
33. Ferreira LR, Frade AF, Santos RH, Teixeira PC, Baron MA, Navarro IC, et al. MicroRNAs miR-1, miR-133a, miR-133b, miR- 208a and miR-208b are dysregulated in chronic chagas disease cardiomyopathy. Int J Cardiol. 2014; 175(3): 409-17.
34. Laugier L, Ferreira LRP, Ferreira FM, Cabantous S, Frade AF, Nunes JP, et al. miRNAs may play a major role in the control of gene expression in key pathobiological processes in Chagas disease cardiomyopathy. PLoS Negl Trop Dis. 2020; 14(12): e0008889.
35. Navarro IC, Ferreira FM, Nakaya HI, Baron MA, Vilar-Pereira G, Pereira IR, et al. MicroRNA transcriptome profiling in heart of Trypanosoma cruzi-infected mice: parasitological and cardiological outcomes. PLoS Negl Trop Dis. 2015; 9(6): e0003828.
36. Ferreira LRP, Ferreira FM, Laugier L, Cabantous S, Navarro IC, Cândido DS, et al. Integration of miRNA and gene expression profiles suggest a role for miRNAs in the pathobiological processes of acute Trypanosoma cruzi infection. Sci Rep. 2017; 7(1): 17990.
37. Jha BK, Varikuti S, Seidler GR, Volpedo G, Satoskar AR, Mc- Gwire BS. MicroRNA-155 deficiency exacerbates Trypanosoma cruzi infection. Infect Immun. 2020; 88(7): e00948-19.
38. Nunes JPS, Andrieux P, Brochet P, Almeida RR, Kitano E, Honda AK, et al. Co-exposure of cardiomyocytes to IFN-γ and TNF-α induces mitochondrial dysfunction and nitro-oxidative stress: implications for the pathogenesis of chronic Chagas disease dardiomyopathy. Front Immunol. 2021; 12: 755862.
39. Torres DJL, Arruda TR, Barros MDS, Gonçales JP, Soares AKA, Oliveira KKDS, et al. Is a negative correlation between sTNFR1 and TNF in patients with chronic Chagas disease the key to clinical progression? Immunobiology. 2021; 227(1): 152166.
40. de Araújo FF, Torres KCL, Peixoto SV, Ribeiro ALP, Mambrini JVM, Rezende VB, et al. CXCL9 and CXCL10 display an agedependent profile in Chagas patients: a cohort study of aging in Bambui, Brazil. Infect Dis Poverty. 2020; 9(1): 51.
41. Vilar-Pereira G, Pereira IR, Ruivo LAS, Moreira OC, da Silva AA, Britto C, at al. Combination chemotherapy with suboptimal doses of Benznidazole and Pentoxifylline sustains partial reversion of experimental Chagas’ heart disease. Antimicrob Agents Chemother. 2016; 60(7): 4297-309.
42. Pedra-Rezende Y, Barbosa JMC, Bombaça ACS, Dantas-Pereira L, Gibaldi D, Vilar-Pereira G, et al. Physical exercise promotes a reduction in cardiac fibrosis in the chronic indeterminate form of experimental Chagas cisease. Front Immunol. 2021; 12: 712034.
43. Farani PSG, Begum K, Vilar-Pereira G, Pereira IR, Almeida IC, Roy S, et al. Treatment with suboptimal dose of Benznidazole mitigates immune response molecular pathways in mice with chronic Chagas cardiomyopathy. Front Cell Infect Microbiol. 2021; 11: 692655.
44. Hasslocher-Moreno AM, Saraiva RM, Sangenis LHC, Xavier SS, de Sousa AS, Costa AR, et al. Benznidazole decreases the risk of chronic Chagas disease progression and cardiovascular events: a long-term follow up study. EClinicalMedicine. 2020; 31: 100694.
45. Lazzerini PE, Capecchi PL, Laghi-Pasini F. Long QT syndrome: an emerging role for inflammation and immunity. Front Cardiovasc Med. 2015; 2: 26.
46. Soeiro MNC. Perspectives for a new drug candidate for Chagas disease therapy. Mem Inst Oswaldo Cruz. 2022; 117: e220004.
47. Vilar-Pereira G, Carneiro VC, Mata-Santos H, Vicentino AR, Ramos IP, Giarola NL, et al. Resveratrol reverses functional Chagas heart disease in mice. PLoS Pathog. 2016; 12(10): e1005947.
48. Holanda MT, Mediano MFF, Hasslocher-Moreno AM, Gonzaga BMS, Carvalho ACC, Ferreira RR, et al. Effects of selenium treatment on cardiac function in Chagas heart disease: results from the STCC randomized trial. EClinicalMedicine. 2021; 40: 101105.
49. Araujo-Jorge TC, Ferreira RR. Translational research in Chagas disease: perspectives in nutritional therapy emerging from selenium supplementation studies as a complementary treatment. Mem Inst Oswaldo Cruz. 2022; 117: e220001.
50. Shaw SM, Shah MK, Williams SG, Fildes JE. Immunological mechanisms of pentoxifylline in chronic heart failure. Eur J Heart Fail. 2009; 11(2): 113-8.
51. Ronco MT, Manarin R, Francés D, Serra E, Revelli S, Carnovale C. Benznidazole treatment attenuates liver NF-kappaB activity and MAPK in a cecal ligation and puncture model of sepsis. Mol Immunol. 2011; 48(6-7): 867-73.
52. Lima MM, Rocha MO, Nunes MC, Sousa L, Costa HS, Alencar MC, et al. A randomized trial of the effects of exercise training in Chagas cardiomyopathy. Eur J Heart Fail. 2010; 12(8): 866-73.

Financial support: FAPERJ (E-26/210.190/2018), CNPq (BPP-304474/2015-0, BPP 306037/2019-0, INCTV, National Institute for Science and Technology for Vaccines), Grant PAEF2-IOC/Fiocruz, Scientist of the State of Rio de Janeiro/FAPERJ (E-26/202.572/2019).
*This report was presented as a lecture at the “Workshop: molecular mechanisms of trypanocidal and leishmanicidal drugs”.
+ Corresponding author:
Received 20 January 2022
Accepted 26 January 2022

Our Location

Memórias do Instituto Oswaldo Cruz

Av. Brasil 4365, Castelo Mourisco 
sala 201, Manguinhos, 21040-900 
Rio de Janeiro, RJ, Brazil

Tel.: +55-21-2562-1222

This email address is being protected from spambots. You need JavaScript enabled to view it.

Support Program


faperj cnpq capes