Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 118 | 2023
Research Articles

Benznidazole treatment decreases IL-6 levels in Trypanosoma cruzi-infected human adipocytes differentiated from adipose tissue-derived stem cells

Leyllane Rafael Moreira1,2, Ana Carla Silva2, Cíntia Nascimento da Costa Oliveira2, Claudeir Dias da Silva Júnior1,2, Amanda Vasconcelos Nascimento2, Kamila Kássia dos Santos Oliveira2, Ana Karine de Araújo Soares3, Karina Lidianne Alcântara Saraiva4, Milena de Paiva Cavalcanti5, Virginia Maria Barros de Lorena2,+

1Universidade Federal de Pernambuco, Programa de Pós-Graduação em Medicina Tropical, Recife, PE, Brasil
2Fundação Oswaldo Cruz-Fiocruz, Instituto Aggeu Magalhães, Laboratório de Imunoparasitologia, Recife, PE, Brasil
3Fundação Altino Ventura, Recife, PE, Brasil
4Fundação Oswaldo Cruz-Fiocruz, Instituto Aggeu Magalhães, Núcleo de Plataformas Tecnológicas, Recife, PE, Brasil
5Fundação Oswaldo Cruz-Fiocruz, Instituto Aggeu Magalhães, Departamento de Microbiologia, Recife, PE, Brasil

DOI: 10.1590/0074-02760220295
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ABSTRACT

BACKGROUND Trypanosoma cruzi, which causes Chagas disease (CD), is a versatile haemoparasite that uses several strategies to evade the host’s immune response, including adipose tissue (AT), used as a reservoir of infection. As it is an effective barrier to parasite evasion, the effectiveness of the drug recommended for treating CD, Benznidazole (BZ), may be questionable.
OBJECTIVE To this end, we evaluated the parasite load and immunomodulation caused by BZ treatment in the culture of adipocytes differentiated from human adipose tissue-derived stem cells (ADSC) infected with T. cruzi.
METHODS The ADSC were subjected to adipogenic differentiation. We then carried out four cultures in which we infected the differentiated AT with trypomastigote forms of the Y strain of T. cruzi and treated them with BZ. After the incubation, the infected AT was subjected to quantitative polymerase chain reaction (qPCR) to quantify the parasite load and transmission electron microscopy (TEM) to verify the infection. The supernatant was collected to measure cytokines, chemokines, and adipokines.
FINDINGS We found elevated secretion of IL-6, CXCL-10/IP-10, CCL2/MCP-1, CCL5/RANTES, and leptin in infected fat cells. However, treatment with BZ promoted a decrease in IL-6.
MAIN CONCLUSION Therefore, we believe that BZ has a beneficial role as it reduces inflammation in infected fat cells.

REFERENCES
01. WHO - World Health Organization. Chagas disease (also known as American trypanosomiasis). [Cited 2022 April 13]. Available from: https://www.who.int/news-room/fact-sheets/detail/chagasdisease-( american-trypanosomiasis).
02. Guarner J. Chagas disease as example of a reemerging parasite. Semin Diagn Pathol. 2019; 36(3): 164-9.

03. Pérez-Molina JA, Molina I. Chagas disease. Lancet. 2018; 391(10115): 82-94.

04. Urbina JA. Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Trop. 2010; 115(1- 2): 55-68.

05. Juiz NA, Estupiñán E, Hernández D, Garcilarzo A, Chadi R, Sanfurgo GM, et al. Association study between CCR2-CCR5 genes polymorphisms and chronic Chagas heart disease in Wichi and in admixed populations from Argentina. PLoS Negl Trop Dis. 2019; 13(1): e0007033.

06. Acevedo GR, Girard MC, Gómez KA. The unsolved jigsaw puzzle of the immune response in Chagas disease. Front Immunol. 2018; 9: 1929.

07. Ferreira AV, Segatto M, Menezes Z, Macedo AM, Gelape C, Andrade LO, et al. Evidence for Trypanosoma cruzi in adipose tissue in human chronic Chagas disease. Microbes Infect. 2011; 13(12- 13): 1002-5.

08. Nagajyothi F, Machado FS, Burleigh BA, Jelicks L, Scherer P, Mukherjee S, et al. Mechanisms of Trypanosoma cruzi persistence in Chagas disease. Cell Microbiol. 2012; 14(5): 634-43.

09. Tanowitz HB, Scherer PE, Mota MM, Figueiredo LM. Adipose tissue: a safe haven for parasites? Trends Parasitol. 2017; 33(4): 276-84.

10. Barthelemy J, Bogard G, Wolowczuk I. Beyond energy balance regulation: the underestimated role of adipose tissues in host defense against pathogens. Front Immunol. 2023; 14: 1083191.

11. Frigolet ME, Gutiérrez-Aguilar R. The colors of adipose tissue. Los colores del tejido adiposo. Gac Med Mex. 2020; 156(2): 142-9.

12. Berry DC, Jiang Y, Graff JM. Emerging roles of adipose progenitor cells in tissue development, homeostasis, expansion and thermogenesis. Trends Endocrinol Metab. 2016; 27(8): 574-85.

13. Kumari M, Heeren J, Scheja L. Regulation of immunometabolism in adipose tissue. Semin Immunopathol. 2018; 40(2): 189-202.

14. Shoemaker JP, Hoffman Jr RV, Huffman DG. Trypanosoma cruzi: preference for brown adipose tissue in mice by the Tulahuen strain. Exp Parasitol. 1970; 27(3): 403-7.

15. Combs TP, Nagajyothi, Mukherjee S, De Almeida CJG, Jelicks LA, Schubert W, et al. The adipocyte as an important target cell for Trypanosoma cruzi infection. J Biol Chem. 2005; 280(25): 24085-94.

16. Nagajyothi F, Desruisseaux MS, Machado FS, Upadhya R, Zhao D, Schwartz GJ, et al. Response of adipose tissue to early infection with Trypanosoma cruzi (Brazil strain). J Infect Dis. 2012; 205(5): 830-40.

17. Nagajyothi F, Desruisseaux MS, Thiruvur N, Weiss LM, Braunstein VL, Albanese C, et al. Trypanosoma cruzi infection of cultured adipocytes results in an inflammatory phenotype. Obesity (Silver Spring). 2008; 16(9): 1992-7.

18. Romanha AJ, de Castro SL, Soeiro MNC, Lannes-Vieira J, Ribeiro I, Talvani A, et al. In vitro and in vivo experimental models for drug screening and development for Chagas disease. Mem Inst Oswaldo Cruz. 2010; 105(2): 233-8.

19. Costa-Oliveira CND, Paiva-Cavalcanti M, Barros MDS, Nakazawa M, Melo MGN, Pessoa-e-Silva R, et al. Outbreak of Chagas disease in Brazil: validation of a molecular diagnostic method. Exp Parasitol. 2023; 247: 108478.

20. Rutkowski JM, Stern JH, Scherer PE. The cell biology of fat expansion. J Cell Biol. 2015; 208(5): 501-12.

21. Rashnonejad A, Ercan G, Gunduz C, Akdemir A, Tiftikcioglu YO. Comparative analysis of human UCB and adipose tissue derived mesenchymal stem cells for their differentiation potential into brown and white adipocytes. Mol Biol Rep. 2018; 45(3): 233-44.

22. Viglietti AIP, Giambartolomei GH, Quarleri J, Delpino MV. Brucella abortus infection modulates 3T3-L1 adipocyte inflammatory response and inhibits adipogenesis. Front Endocrinol (Lausanne). 2020; 11: 585923.

23. Basolo A, Poma AM, Bonuccelli D, Proietti A, Macerola E, Ugolini C, et al. Adipose tissue in COVID-19: detection of SARSCoV- 2 in adipocytes and activation of the interferon-alpha response. J Endocrinol Invest. 2022; 45(5): 1021-9.

24. Ryan PM, Caplice NM. Is adipose tissue a reservoir for viral spread, immune activation, and cytokine amplification in Coronavirus disease 2019? Obesity (Silver Spring). 2020; 28(7):1191-4.

25. Schwing A, Pisani DF, Pomares C, Majoor A, Lacas-Gervais S, Jager J, et al. Identification of adipocytes as target cells for Leishmania infantum parasites. Sci Rep. 2021; 11(1): 21275.

26. Kratz JM, Bournissen FG, Forsyth CJ, Sosa-Estani S. Clinical and pharmacological profile of benznidazole for treatment of Chagas disease. Expert Rev Clin Pharmacol. 2018; 11(10): 943-57.

27. Soares AKA, Neves PAF, Nascimento AV, Esmeraldo AAM, Moreira LR, Higino TMM, et al. Benznidazole: hero or villain of cellular immune response in chronic Chagas disease patients? Immunobiology. 2021; 226(1): 152046.

28. Moreira LR, Oliveira KKS, Torres DJL, Barros MS, de Arruda TR, Nascimento AV, et al. Benzonidazole treatment has a beneficial effect on cells infected with the Colombian strain of Trypanosoma cruzi. Parasite Immunol. 2023; 45(6): e12983.

29. Xue W, Fan Z, Li L, Lu J, Zhai Y, Zhao J. The chemokine system and its role in obesity. J Cell Physiol. 2019; 234(4): 3336-46.

30. Sokol CL, Luster AD. The chemokine system in innate immunity. Cold Spring Harb Perspect Biol. 2015; 7(5): a016303.
31. Albareda MC, Natale MA, De Rissio AM, Fernandez M, Serjan A, Alvarez MG, et al. Distinct treatment outcomes of antiparasitic therapy in Trypanosoma cruzi-infected children is associated with early changes in cytokines, chemokines, and T-Cell phenotypes. Front Immunol. 2018; 9: 1958.
32. Rodríguez-Angulo H, Marques J, Mendoza I, Villegas M, Mijares A, Gironès N, et al. Differential cytokine profiling in Chagasic patients according to their arrhythmogenic-status. BMC Infect Dis. 2017; 17(1): 221.
33. Cabalén ME, Cabral MF, Sanmarco LM, Andrada MC, Onofrio LI, Ponce NE, et al. Chronic Trypanosoma cruzi infection potentiates adipose tissue macrophage polarization toward an anti-inflammatory M2 phenotype and contributes to diabetes progression in a dietinduced obesity model. Oncotarget. 2016; 7(12): 13400-15.
34. González FB, Villar SR, Toneatto J, Pacini MF, Márquez J, D’Attilio L, et al. Immune response triggered by Trypanosoma cruzi infection strikes adipose tissue homeostasis altering lipid storage, enzyme profile and adipokine expression. Med Microbiol Immunol. 2019; 208(5): 651-66.
35. 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. 2015; 6(1): 12-22.
36. Scherer PE. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes. 2006; 55(6): 1537-45.
37. Frühbeck G, Catalán V, Rodríguez A, Gómez-Ambrosi J. Adiponectin- leptin ratio: a promising index to estimate adipose tissue dysfunction. Relation with obesity-associated cardiometabolic risk. Adipocyte. 2018; 7(1): 57-62.
38. Wueest S, Laesser CI, Böni-Schnetzler M, Item F, Lucchini FC, Borsigova M, et al. IL-6-Type cytokine signaling in adipocytes induces intestinal GLP-1 secretion. Diabetes. 2018; 67(1): 36-45.
39. González F, Villar S, D’Attilio L, Leiva R, Marquez J, Lioi S, et al. Dysregulated network of immune, endocrine and metabolic markers is associated to more severe human chronic Chagas cardiomyopathy. Neuroimmunomodulation. 2018; 25(3): 119-28.
40. Fernandes F, Dantas S, Ianni BM, Ramires FJ, Buck P, Salemi VM, et al. Leptin levels in different forms of Chagas’ disease. Braz J Med Biol Res. 2007; 40(12): 1631-6.

doi: 10.1590/0074-02760220295
+ Corresponding author: virginia.lorena@fiocruz.br
ORCID https://orcid.org/ 0000-0003-0663-236X
Received 30 December 2022
Accepted 27 September 2023

HOW TO CITE
Moreira LR, Silva AC, Costa-Oliveira CN, Silva-Júnior CD, Nascimento AV, Oliveira KKS, et al. Benznidazole treatment decreases IL-6 levels in Trypanosoma cruzi-infected human adipocytes differentiated from adipose tissue-derived stem cells. Mem Inst Oswaldo Cruz. 2023; 118: e220295.

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