Hostname: page-component-cd9895bd7-jn8rn Total loading time: 0 Render date: 2024-12-18T14:12:37.491Z Has data issue: false hasContentIssue false
  • English
  • Français

Therapeutic responses to different anti-Trypanosoma cruzi drugs in experimental infection by benznidazole-resistant parasite stock

Published online by Cambridge University Press:  21 July 2014

SÉRGIO CALDAS ,
IVO SANTANA CALDAS ,
ALZIRA BATISTA CECÍLIO ,
LÍVIA DE FIGUEIREDO DINIZ ,
ANDRÉ TALVANI ,
ISABELA RIBEIRO  and
MARIA TEREZINHA BAHIA
SÉRGIO CALDAS
Affiliation:
Laboratório de Doença de Chagas, Departamento de Ciências Biológicas and Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, MG, 35400-000, Brazil Fundação Ezequiel Dias, Rua Conde Pereira Carneiro, 80, Gameleira, Belo Horizonte, Minas Gerais, Brazil
IVO SANTANA CALDAS
Affiliation:
Laboratório de Doença de Chagas, Departamento de Ciências Biológicas and Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, MG, 35400-000, Brazil Departamento de Patologia e Parasitologia, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, MG, Brazil
ALZIRA BATISTA CECÍLIO
Affiliation:
Fundação Ezequiel Dias, Rua Conde Pereira Carneiro, 80, Gameleira, Belo Horizonte, Minas Gerais, Brazil
LÍVIA DE FIGUEIREDO DINIZ
Affiliation:
Laboratório de Doença de Chagas, Departamento de Ciências Biológicas and Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, MG, 35400-000, Brazil
ANDRÉ TALVANI
Affiliation:
Laboratório de Doença de Chagas, Departamento de Ciências Biológicas and Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, MG, 35400-000, Brazil
ISABELA RIBEIRO
Affiliation:
Drugs for Neglected Disease initiative (DNDi), 1202 Geneva, Switzerland
MARIA TEREZINHA BAHIA*
Affiliation:
Laboratório de Doença de Chagas, Departamento de Ciências Biológicas and Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro, Ouro Preto, MG, 35400-000, Brazil
*
*Corresponding author: Laboratório de Doença de Chagas, sala 39, Instituto de Ciências Biológicas, ICEB II, Universidade Federal de Ouro Preto, Ouro Preto, MG, 35400-000, Brazil. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

This study describes the role of parasite clearance time induced by benznidazole, fexinidazole and posaconazole treatments upon mice infection with a benznidazole-resistant Trypanosoma cruzi strain in the pathological outcomes. Trypanosoma cruzi-infected mice were treated with different drugs and parasite clearance time was detected by blood and tissue qPCR, to determine the dynamic relationship between the efficacy of the treatments and the intensity of heart lesion/serum inflammatory mediators. Our results indicate that anti-T. cruzi treatments were able to reduce parasite replication and consequently induce immunomodulatory effects, where the degree of the immunopathology prevention was related to the time of parasite clearance induced by different treatments. Nevertheless, in benznidazole and posaconazole treatments, parasite rebounding was detected with parasitism reaching levels similar to infected and non-treated mice; the time for parasitic rebound being earlier among benznidazole-treated mice. In parallel, an increase of cardiac lesions and plasma chemokine levels was also detected and was more accentuated in benznidazole-treated animals. Interestingly, in the presence of parasitological cure (fexinidazole treatment), basal levels of these inflammatory mediators were evidenced as well as an absence of cardiac inflammation or fibrosis. Overall, our data indicate that all treatments have positive effects on the clinical evolution of T. cruzi infection, with success in preventing cardiac alterations being drug-dependent.

Keywords

Trypanosoma cruzireal-time PCRchemotherapyinflammationbenznidazoleposaconazolefexinidazole
Type
Research Article
Information
Parasitology , Volume 141 , Issue 12 , October 2014 , pp. 1628 - 1637
Check for updates
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Aliberti, J. C., Machado, F. S., Souto, J. T., Campanelli, A. P., Teixeira, M. M., Gazzinelli, R. T. and Silva, J. S. (1999). Beta-chemokines enhance parasite uptake and promote nitric oxide-dependent microbiostatic activity in murine inflammatory macrophages infected with Trypanosoma cruzi. Infection and Immunity 67, 4819–4826.Google Scholar
Andrade, S. G., Stocker-Guerret, S., Pimentel, A. S. and Grimaud, J. A. (1991). Reversibility of cardiac fibrosis in mice chronically infected with Trypanosoma cruzi, under specific chemotherapy. Memórias do Insituto Oswaldo Cruz 86, 187–200.CrossRefGoogle ScholarPubMed
Ãnez, N., Carrasco, H., Parada, H., Crisante, G., Rojas, A., Fuenmayor, C., Gonzales, N., Percoco, G., Borges, R., Guevara, P. and Ramirez, J. L. (1999). Myocardial parasite persistence in chronic chagasic patients. American Journal of Medicine and Tropical Hygiene 60, 726–732.CrossRefGoogle ScholarPubMed
Bahia, M. T., de Andrade, I. M., Martins, T. A., Nascimento, A. F. S., Diniz, L. F., Caldas, I. S., Talvani, A., Trunz, B. B., Torreele, E. and Ribeiro, I. (2012). Fexinidazole: a potential new drug candidate for Chagas disease. PLOS Neglected Tropical Diseases 6, e1870.Google Scholar
Bahia, M. ., Nascimento, A. F., Mazzeti, A. L., Marques, L. F., Gonçalves, K. R., Mota, L. W., Diniz, L. F., Caldas, I. S., Talvani, A., Shackleford, D. M., Koltun, M., Saunders, J., White, K. L., Scandale, I., Charman, S. A. and Chatelain, E. (2014). Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease. Antimicrobial Agents and Chemotherapy. Epub ahead of print. doi: 10.1128/AAC.02754-13.CrossRefGoogle ScholarPubMed
Brener, Z. (1962). Therapeutic activity and criterion of cure on mice experimentally infected with Trypanosoma cruzi. Revista Instituto de Medicina Tropical de São Paulo 4, 389–396.Google Scholar
Caldas, I. S., Talvani, A., Caldas, S., Carneiro, C., de Lana, M., Guedes, P. M. M. and Bahia, M. T. (2008). Benznidazole therapy during acute phase of Chagas disease reduces parasite load but does not prevent chronic cardiac lesions. Parasitology Research 103, 413–421.CrossRefGoogle Scholar
Caldas, S., Caldas, I. S., Diniz, L. F., Lima, W. G., Oliveira, R. de P., Cecílio, A. B., Ribeito, A., Talvani, A. and Bahia, M. T. (2012). Real-time PCR strategy for parasite quantification in blood and tissue samples of experimental Trypanosoma cruzi infection. Acta Tropica 123, 170–177.Google Scholar
Cançado, J. R. (2000). Long term evaluation of etiological treatment of Chagas disease with benznidazole. Revista do Instituto de Medicina Tropical de São Paulo 44, 29–37.CrossRefGoogle Scholar
Cook, D. N., Smithies, O., Strieter, R. M., Frelinger, J. A. and Serody, J. S. (1999). CD8+ T cells are a biologically relevant source of macrophage inflammatory protein-1 alpha in vivo. Journal of Immunology 162, 5423–5428.Google Scholar
Cummings, K. L. and Tarleton, R. L. (2003). Rapid quantitation of Trypanosoma cruzi in host tissue by real-time PCR. Molecular and Biochemical Parasitology 129, 53–59.Google Scholar
Diniz, L. F., Caldas, I. S., Guedes, P. M. M., Crepalde, G. P., de Lana, M., Carneiro, C. M., Talvani, A., Urbina, J. A. and Bahia, M. T. (2010). Effects of ravuconazole treatment on parasite load and immune response in dogs experimentally infected with Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 54, 2979–2986.CrossRefGoogle ScholarPubMed
Diniz, L. F., Urbina, J. A., de Andrade, I. M., Mazzetti, A. L., Martins, T. A. F., Caldas, I. S., Talvani, A., Ribeiro, I. and Bahia, M. T. (2013). Benznidazole and posaconazole in experimental Chagas disease: positive interaction in concomitant and sequential treatments. PLOS Neglected Tropical Diseases 7, e2367.Google Scholar
Docampo, R. and Moreno, S. N. J. (1986). Free-radical metabolism of antiparasitic agents. Federation Proceedings 45, 2471–2476.Google ScholarPubMed
Filardi, L. S. and Brener, Z. (1987). Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease. Transactions of the Royal Society of Tropical Medicine and Hygiene 81, 755–759.CrossRefGoogle ScholarPubMed
Garcia, S., Ramos, C. O., Senra, J. F., Vilas-Boas, F., Rodrigues, M. M., Campos-de-Carvalho, A. C., Ribeiro-Dos-Santos, R. and Soares, M. B. (2005). Treatment with benznidazole during the chronic phase of experimental Chagas disease decreases cardiac alterations. Antimicrobial Agents and Chemotherapy 49, 1521–1528.CrossRefGoogle ScholarPubMed
Guedes, P. M. M., Urbina, J. A., de Lana, M., Afonso, L. C., Veloso, V. M., Tafuri, W. L., Machado-Coelho, G. L., Chiari, E. and Bahia, M. T. (2004). Activity of the new triazole derivative albaconazole against Trypanosoma (Schizotrypanum) cruzi in dog hosts. Antimicrobial Agents and Chemotherapy 48, 4286–4292.CrossRefGoogle ScholarPubMed
Hardison, J. L., Wrightsman, R. A., Carpenter, P. M., Kuziel, W. A., Lane, T. E. and Manning, J. E. (2006). 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.Google Scholar
Hall, B. S. and Wilkinson, S. R. (2011). Activation of benznidazole by trypanosomal type I nitroreductases results in glyoxal formation. Antimicrobial Agents and Chemotherapy 56, 115–123.Google Scholar
Machado, F. S., Martins, G. A., Aliberti, J. C., Mestriner, F. L., Cunha, F. Q. and Silva, J. S. (2000). Trypanosoma cruzi-infected cardiomyocytes produce chemokines and cytokines that trigger potent nitric oxide-dependent trypanocidal activity. Circulation 102, 3003–3008.Google Scholar
Machado, F. S., Souto, J. T., Rossi, M. A., Esper, L., Tanowitz, H. B., Aliberti, J. and Silva, J. S. (2008). Nitric oxide synthase-2 modulates chemokine production by Trypanosoma cruzi-infected cardiac myocytes. Microbes and Infection 10, 1558–1566.Google Scholar
Molina, J., Martins-Filho, O., Brener, Z., Romanha, A. J., Loebenberg, D. and Urbina, J. A. (2000). Activities of the triazole derivative SCH 56592 (posaconazole) against drug-resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine hosts. Antimicrobial Agents and Chemotherapy 44, 150–155.CrossRefGoogle ScholarPubMed
Paiva, C. N., Figueiredo, R. T., Kroll-Palhares, K., Silva, A. A., Silvério, J. C., Gibaldi, D., Pyrrho Ados, S., Benjamim, C. F., Lannes-Vieira, J. and Bozza, M. T. (2009). CCL2/MCP-1 controls parasite burden, cell infiltration, and mononuclear activation during acute Trypanosoma cruzi infection. Journal of Leukocyte Biology 86, 1239–1246.Google Scholar
Pinazo, M. J., Espinosa, G., Gállego, M., López-Chejade, P. L., Urbina, J. A. and Gascón, J. (2010). Successful treatment with posaconazole of a patient with chronic Chagas disease and systemic lupus erythematosus. American Journal of Tropical Medicine and Hygiene 82, 583–587.CrossRefGoogle ScholarPubMed
Raether, W. and Seidenath, H. (1983). The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica. Annals of Tropical Medicine and Parasitology 77, 13–26.Google Scholar
Sallusto, F., LanzaVecchia, A. and Mackay, C. R. (1998). Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunology Today 19, 568–574.CrossRefGoogle ScholarPubMed
Santos, F. M., de Lima, W. G., Gravel, A., Martins, T. A., Talvani, A., Torres, R. M. and Bahia, M. T. (2012). Cardiomyopathy prognosis after benznidazole treatment in chronic canine Chagas' disease. Journal of Antimicrobial Chemotherapy 68, 1–9.Google Scholar
Sokolova, A. Y., Wyllie, S., Patterson, S., Oza, S. L., Read, K. D. and Fairlamb, A. H. (2010). Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis. Antimicrobial Agents and Chemotherapy 54, 2893–2900.Google Scholar
Talvani, A., Ribeiro, C. S. and Aliberti, J. C. S. (2000). Kinetics of cytokine genes expression in experimental chagasic cardiomyopathy: a direct correlation between levels of tissue parasitism and chemokine mRNAs expression during infection with Trypanosoma cruzi. Microbes and Infection 2, 851–866.CrossRefGoogle Scholar
Tarleton, R. L. and Zhang, L. (1999). Chagas disease etiology: autoimmunity or parasite persistence? Parasitology Today 15, 94–99.Google Scholar
Tarleton, R. L., Sun, J., Zhang, L. and Postan, M. (1994). Depletion of T-cell subpopulations results in exacerbation of myocarditis and parasitism in experimental Chagas' disease. Infection and Immunity 62, 1820–1829.CrossRefGoogle ScholarPubMed
Torreele, E., Trunz, B. B., Tweats, D., Kaiser, M., Brun, R., Mazué, G., Bray, M. A. and Pécoul, B. (2010). Fexinidazole: a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLOS Neglected Tropical Diseases 4, e923.Google Scholar
Urbina, J. A. (2010). Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Tropica 115, 55–68.Google Scholar
Wilkinson, S. R. and Kelly, J. M. (2009). Trypanocidal drugs: mechanisms, resistance and new targets. Expert Reviews in Molecular Medicine 11, e31.Google Scholar
Workman, P., White, R. A., Walton, M. I., Owen, L. N. and Twentyman, P. R. (1979). Preclinical pharmacokinetics of benznidazole. British Journal of Cancer 50, 291–303.Google Scholar