Benzonidazole treatment has a beneficial effect on cells infected with the Colombian strain of Trypanosoma cruzi.

Publisher: Wiley Country of Publication: England NLM ID: 7910948 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-3024 (Electronic) Linking ISSN: 01419838 NLM ISO Abbreviation: Parasite Immunol Subsets: MEDLINE

Original Publication: Oxford, Wiley

Trypanosoma cruzi* ; Nitroimidazoles*/pharmacology ; Nitroimidazoles*/therapeutic use ; Chagas Disease*/drug therapy ; Trypanocidal Agents*/pharmacology ; Trypanocidal Agents*/therapeutic use; Humans ; Leukocytes, Mononuclear ; Colombia

Benznidazole (Bz) is the recommended drug for the treatment of Chagas disease; however, its efficacy may vary according to the sensitivity of Trypanosoma cruzi strains to the drug and host immune background. The study evaluated the immune response of peripheral blood mononuclear cells (PBMC) that were infected in vitro with the Colombian strain (Col) and treated with Bz. The co-cultures were incubated for 24 h, 5 and 10 days, where cytokine dosage was performed in the supernatant and evaluation of the cells for CD28 ⁺ and CTLA-4 ⁺ molecules in CD4 ⁺ and CD8 ⁺ lymphocytes, and CD80 ⁺ , CD86 ⁺ and HLA-DR ⁺ in CD14 ⁺ cells. The results showed that Col induced a strong inflammatory response, with an increase in IFN-γ and TNF early in the infection (24 h), however, from 5 days of infection on, TNF production declined, and IL-10 production increased, which may be associated with a control mechanism of the exacerbated inflammatory response. The Bz treatment did not significantly alter the frequencies of the phenotypes evaluated both T cell subsets and CD14 ⁺ cells. Therefore, this study reinforces the need for typing the patient's strain to guide therapy and promote individualized treatment protocols due to the heterogeneous genetic background among T. cruzi strains.
(© 2023 John Wiley & Sons Ltd.)

Pérez-Molina JA, Molina I. Chagas disease. Lancet. 2017;6736(17):1-13. doi:10.1016/S0140-6736(17)31612-4.
Zingales B, Miles MA, Campbell DA, et al. The revised Trypanosoma cruzi subspecific nomenclature: rationale, epidemiological relevance and research applications. Infect Genet Evol. 2012;12(2):240-253. doi:10.1016/j.meegid.2011.12.009.
Lima L, Espinosa-Álvarez O, Ortiz PA, et al. Genetic diversity of Trypanosoma cruzi in bats, and multilocus phylogenetic and phylogeographical analyses supporting Tcbat as an independent DTU (discrete typing unit). Acta Trop. 2015;151(1):166-177. doi:10.1016/j.actatropica.2015.07.015.
Tibayrenc M, Ayala FJ. The population genetics of Trypanosoma cruzi revisited in the light of the predominant clonal evolution model. Acta Trop. 2015;151(1):156-165. doi:10.1016/j.actatropica.2015.05.006.
Dutra WO, Menezes CA, Magalhães LM, Gollob KJ. Immunoregulatory networks in human Chagas disease. Parasite Immunol. 2014;36(8):377-387. doi:10.1111/pim.12107.
Zingales B, Andrade SG, Briones MR, et al. A new consensus for Trypanosoma cruzi intraspecific nomenclature: second revision meeting recommends TcI to TcVI. Mem Inst Oswaldo Cruz. 2009;104(7):1051-1054. doi:10.1590/S0074-02762009000700021.
Brenière SF, Waleckx E, Barnabé C. Over six thousand Trypanosoma cruzi strains classified into discrete typing units (DTUs): attempt at an inventory. PLoS Negl Trop Dis. 2016;10(8):1-19. doi:10.1371/journal.pntd.0004792.
Pinazo MJ, Gascon J. The importance of the multidisciplinary approach to deal with the new epidemiological scenario of Chagas disease (global health). Acta Trop. 2015;151(1):16-20. doi:10.1016/j.actatropica.2015.06.013.
Andrade V, Barral-Netto M, Andrade SG. Patterns of resistance of inbred mice to Trypanosoma cruzi are determined by parasite strain. Braz J Med Biol Res. 1985;18(4):499-506.
Andrade LO, Galvão LM, Meirelles Mde N, Chiari E, Pena SD, Macedo AM. Differential tissue tropism of Trypanosoma cruzi strains: an in vitro study. Mem Inst Oswaldo Cruz. 2010;105(6):834-837. doi:10.1590/S0074-02762010000600018.
Filardi LS, Brener Z. Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease. Trans R Soc Trop Med Hyg. 1987;81(5):755-759. doi:10.1016/0035-9203(87)90020-4.
Camandaroba EL, Campos RF, Magalhães JB, Andrade SG. Clonal structure of Trypanosoma cruzi Colombian strain (biodeme type III): biological, isoenzymic and histopathological analysis of seven isolated clones. Rev Soc Bras Med Trop. 2001;34(2):151-157.
Wilkinson SR, Taylor MC, Horn D, Kelly JM, Cheeseman I. A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes. Proc Natl Acad Sci U S A. 2008;105(13):5022-5027. doi:10.1073/pnas.0711014105.
Viotti R, Gabriela M, Petti M, Armenti A. Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Rev Anti Infect Ther. 2009;7(2):157-163. doi:10.1586/14787210.7.2.157.
Cevey ÁC, Mirkin GA, Penas FN, Goren NB. Low-dose benznidazole treatment results in parasite clearance and attenuates heart inflammatory reaction in an experimental model of infection with a highly virulent Trypanosoma cruzi strain. Int J Parasitol Drugs Drug Resist. 2016;6(1):12-22. doi:10.1016/j.ijpddr.2015.12.001.
Molina I, Prat JG, Salvador F, et al. Randomized trial of Posaconazole and benznidazole for chronic Chagas' disease. N Engl J Med 2014. 2014;370(20):1899-1908. doi:10.1056/NEJMoa1313122.
Campi-Azevedo AC, Gomes JAS, Teixeira-Carvalho A, et al. Etiological treatment of Chagas disease patients with benznidazole lead to a sustained pro-inflammatory profile counterbalanced by modulatory events. Immunobiology. 2015;220(5):564-574. doi:10.1016/j.imbio.2014.12.006.
Coura JR, De CSL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz. 2002;97(January):3-24. doi:10.1590/S0074-02762002000100001.
Sathler-avelar R, Vitelli-avelar DM, Elói-santos SM, Gontijo ED, Andréa Teixeira-Carvalho OAM-F. Blood leukocytes from benznidazole-treated indeterminate chagas disease patients display an overall type-1-modulated cytokine profile upon short-term in vitro stimulation with Trypanosoma cruzi antigens. BMC Infect Dis. 2012;12:123. doi:10.1186/1471-2334-12-123.
Albareda MC, Laucella SA. Modulation of Trypanosoma cruzi-specific T-cell responses after chemotherapy for chronic Chagas disease. Mem Inst Oswaldo Cruz. 2015;110(3):414-421. doi:10.1590/0074-02760140386.
Soares AKA, Neves PAF, Nascimento AV, et al. Benznidazole: hero or villain of cellular immune response in chronic Chagas disease patients? Immunobiology. 2021;226(1):152046. doi:10.1016/j.imbio.2020.152046.
Romanha AJ, de Castro SL, Soeiro M d NC, et al. In vitro and in vivo experimental models for drug screening and development for Chagas disease. Mem Inst Oswaldo Cruz. 2010;105(2):233-238. doi:10.1590/S0074-02762010000200022.
Aggarwal BB, Natarajan K. Tumor necrosis factors: developments during the last decade. Eur Cytokine Netw. 1996;7(2):93-124.
Lima EC, Garcia I, Vicentelli MH, Vassalli P, Minoprio P. Evidence for a protective role of tumor necrosis factor in acute phase of Trypanosoma cruzi infection in mice. Infect Immun. 1997;65(2):457-465. doi:10.1128/IAI.65.2.457-465.1997.
Machado FS, Martins GA, Aliberti JC, Mestriner FL, Cunha FQ, Silva JS. Trypanosoma cruzi-infected cardiomyocytes produce chemokines and cytokines that trigger potent nitric oxide-dependent trypanocidal activity. Circulation. 2000;102(24):3003-3008. doi:10.1161/01.CIR.102.24.3003.
Kayama H, Takeda K. The innate immune response to Trypanosoma cruzi infection. Microbes Infect. 2010;12(7):511-517. doi:10.1016/j.micinf.2010.03.005.
Ferreira RC, Ianni BM, Abel LCJ, et al. Increased plasma levels of tumor necrosis factor- α in asymptomatic/“indeterminate ” and Chagas disease cardiomyopathy patients. Mem Inst Oswaldo Cruz. 2003;98(April):407-411. doi:10.1590/S0074-02762003000300021.
Pérez-Fuentes R, Guégan JF, Barnabé C, et al. Severity of chronic Chagas disease is associated with cytokine/antioxidant imbalance in chronically infected individuals. Int J Parasitol. 2003;33(3):293-299. doi:10.1016/S0020-7519(02)00283-7.
Talvani A, Rocha MO, Barcelos LS, Gomes YM, Ribeiro AL, Teixeira MM. Elevated concentrations of CCL2 and tumor necrosis factor-alpha in chagasic cardiomyopathy. Clin Infect Dis. 2004;38(7):943-950. doi:10.1086/381892.
Magalhães LMD, Viana A, Chiari E, Galvão LMC, Gollob KJ, Dutra WO. Differential activation of human monocytes and lymphocytes by distinct strains of Trypanosoma cruzi. PLoS Negl Trop Dis. 2015;9(7):1-17. doi:10.1371/journal.pntd.0003816.
Poveda C, Fresno M, Girónes N, et al. Cytokine profiling in Chagas disease: towards understanding the association with infecting Trypanosoma cruzi discrete typing units (A BENEFIT TRIAL Sub-Study). PLoS One. 2014;9(3):1-8.
Silva JS, Aliberti JC, Martins GA, Souza MA, Souto JT, Pádua MA. The role of IL-12 in experimental Trypanosoma cruzi infection. Braz J Med Biol Res. 1998;31:111-115. doi:10.1590/s0100-879x1998000100014.
Van Overtvelt L, Vanderheyde N, Verhasselt V, et al. Trypanosoma cruzi infects human dendritic cells and prevents their maturation: inhibition of cytokines, HLA-DR, and costimulatory molecules. Infect Immun. 1999;67(8):4033-4040. doi:10.1128/IAI.67.8.4033-4040.1999.
Van Overtvelt L, Andrieu M, Verhasselt V, et al. Trypanosoma cruzi down-regulates lipopolysaccharide-induced MHC class I on human dendritic cells and impairs antigen presentation to specific CD8+ T lymphocytes. Int Immunol. 2002;14(10):1135-1144. doi:10.1093/intimm/dxf077.
Brodskyn C, Patricio J, Oliveira R, et al. Glycoinositolphospholipids from Trypanosoma cruzi interfere with macrophages and dendritic cell responses. Infect Immun. 2002;70(7):3736-3743. doi:10.1128/IAI.70.7.3736-3743.2002.
Zambrano-Villa S, Rosales-Borjas D, Carrero JC, Ortiz-Ortiz L. How protozoan parasites evade the immune response. Trends Parasitol. 2002;18(6):272-278. doi:10.1016/s1471-4922(02)02289-4.
Marinho CR, Nuñez-Apaza LN, Martins-Santos R, et al. IFN-gamma, but not nitric oxide or specific IgG, is essential for the in vivo control of low-virulence Sylvio X10/4 Trypanosoma cruzi parasites. Scand J Immunol. 2007;66(2-3):297-308. doi:10.1111/j.1365-3083.2007.01958.x.
Laucella SA, Mazliah DP, Bertocchi G, et al. Changes in Trypanosoma cruzi-specific immune responses after treatment: surrogate markers of treatment efficacy. Clin Infect Dis. 2009;49(11):1675-1684. doi:10.1086/648072.
Gomes JA, Bahia-Oliveira LM, Rocha MO, Martins-Filho OA, Gazzinelli G, Correa-Oliveira R. Evidence that development of severe cardiomyopathy in human Chagas' disease is due to a Th1-specific immune response. Infect Immun. 2003;71(3):1185-1193. doi:10.1128/IAI.71.3.1185-1193.2003.
D'Ávila DA, Guedes PM, Castro AM, Gontijo ED, Chiari E, Galvão LMC. Immunological imbalance between IFN-gamma and IL−10 levels in the sera of patients with the cardiac form of Chagas disease. Mem Inst Oswaldo Cruz. 2009;104(1):100-105. doi:10.1590/S0074-02762009000100015.
De Oliveira MT, Taciana K, Silva S, et al. Differential expression of proteins in genetically distinct Trypanosoma cruzi samples (TcI and TcII DTUs) isolated from chronic Chagas disease cardiac patients. Parasite Vector. 2018;11(611):1-11. doi:10.1186/s13071-018-3181-1.
Abbas AK, Trotta E, Simeonov DR, Marson A, Bluestone JA. Revisiting IL-2: biology and therapeutic prospects. Sci Immunol. 2018;3(25):eaat1482. doi:10.1126/sciimmunol.aat1482.
Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol. 2001;1(3):220-228. doi:10.1038/35105024.
Rudd CE, Taylor A, Schneider H, Europe PMC Funders Group. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2014;229(1):12-26.
Soares AKA, Neves PAF, Cavalcanti MGAM, et al. Expression of co-stimulatory molecules CD80 and CD86 is altered in CD14 + HLA-DR + monocytes from patients with Chagas disease following induction by Trypanosoma cruzi recombinant antigens. Rev Soc Bras Med Trop 2016. 2016;49(5):632-636. doi:10.1590/0037-8682-0149-2016.
Souza PE, Rocha MO, Menezes CA, et al. Trypanosoma cruzi infection induces differential modulation of costimulatory molecules and cytokines by monocytes and T cells from patients with indeterminate and cardiac Chagas' disease. Infect Immun. 2007;75(4):1886-1894. doi:10.1128/IAI.01931-06.
La Flamme AC, Kahn SJ, Rudensky AY, Van Voorhis WC. Trypanosoma cruzi-infected macrophages are defective in major histocompatibility complex class II antigen presentation. Eur J Immunol. 1997;27(12):3085-3094. doi:10.1002/eji.1830271202.
Souza PE, Rocha MO, Rocha-Vieira E, et al. Monocytes from patients with indeterminate and cardiac forms of Chagas' disease display distinct phenotypic and functional characteristics associated with morbidity. Infect Immun. 2004;72(9):5283-5291. doi:10.1128/IAI.72.9.5283-5291.2004.

Keywords: DTU; Trypanosoma cruzi; benznidazole; immune response; immunomodulation

YC42NRJ1ZD (benzonidazole)
0 (Nitroimidazoles)
0 (Trypanocidal Agents)

Date Created: 20230417 Date Completed: 20230519 Latest Revision: 20230525

20250114

10.1111/pim.12983

37066749