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Challenges in Response to Treatment Evaluation and Progression of the Disease

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Chagas Disease

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Abstract

Chagas disease pathology presents itself in two successive phases: an acute and a chronic phase that can last decades. Most patients remain in a clinically silent asymptomatic chronic stage which can lead to a symptomatic chronic phase that is primarily characterized by cardiac alterations. Treatment during the chronic phase of the disease is recommended. Antiparasitic treatment efficacy in chronic Chagas disease can only be measured through seroconversion of conventional serological tests which may take several years or decades to assess. Many efforts are being made to identify serological biomarkers that allow evaluation of the treatment efficacy in a short period of time, providing information on the progression of the disease.

Control of T. cruzi infection requires the activation of both CD4+ and CD8+ T cells. Several findings indicate that the functional and phenotypic cellular pattern of T cells is modified during the evolution of chronic Chagas disease. Thus, a dysfunctional response of the T cells showing a diminished capacity to multifunctional activity, together with an increase in the inhibitory receptors coexpression, is observed to be associated with the progression of the disease. Therapeutic treatment improves the functionality of these antigen-specific T cells by the partial reversion of the cell exhaustion process.

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References

  1. Mateus J, Perez-Anton E, Lasso P, Egui A, Roa N, Carrilero B, Gonzalez JM, Thomas MC, Puerta CJ, Lopez MC, Cuellar A. Antiparasitic treatment induces an improved CD8+ T cell response in chronic chagasic patients. J Immunol. 2017;198:3170. https://doi.org/10.4049/jimmunol.1602095.

    Article  PubMed  CAS  Google Scholar 

  2. 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(10):724–34.

    Article  PubMed  CAS  Google Scholar 

  3. Viotti R, Vigliano C, Alvarez MG, Lococo B, Petti M, Bertocchi G, Armenti A, De Rissio AM, Cooley G, Tarleton R, Laucella S. Impact of aetiological treatment on conventional and multiplex serology in chronic Chagas disease. PLoS Negl Trop Dis. 2011;5(9):e1314. https://doi.org/10.1371/journal.pntd.0001314.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cooley G, Etheridge RD, Boehlke C, Bundy B, Weatherly DB, Minning T, Haney M, Postan M, Laucella S, Tarleton RL. High throughput selection of effective serodiagnostics for Trypanosoma cruzi infection. PLoS Negl Trop Dis. 2008;2(10):e316. https://doi.org/10.1371/journal.pntd.0000316.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Granjon E, Dichtel-Danjoy ML, Saba E, Sabino E, Campos de Oliveira L, Zrein M. Development of a novel multiplex immunoassay multi-cruzi for the serological confirmation of Chagas disease. PLoS Negl Trop Dis. 2016;10(4):e0004596. https://doi.org/10.1371/journal.pntd.0004596.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Zrein M, Granjon E, Gueyffier L, Caillaudeau J, Liehl P, Pottel H, Cardoso CS, Oliveira CDL, de Oliveira LC, Lee TH, Ferreira AM, Ribeiro ALP, Busch MP, Sabino EC. A novel antibody surrogate biomarker to monitor parasite persistence in Trypanosoma cruzi-infected patients. PLoS Negl Trop Dis. 2018;12(2):e0006226. https://doi.org/10.1371/journal.pntd.0006226.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Fernandez-Villegas A, Pinazo MJ, Maranon C, Thomas MC, Posada E, Carrilero B, Segovia M, Gascon J, Lopez MC. Short-term follow-up of chagasic patients after benzonidazole treatment using multiple serological markers. BMC Infect Dis. 2011;11:206. https://doi.org/10.1186/1471-2334-11-206.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Fernandez-Villegas A, Thomas MC, Carrilero B, Tellez C, Maranon C, Murcia L, Moralo S, Alonso C, Segovia M, Lopez MC. The innate immune response status correlates with a divergent clinical course in congenital Chagas disease of twins born in a non-endemic country. Acta Trop. 2014;140:84–90. https://doi.org/10.1016/j.actatropica.2014.08.006.

    Article  PubMed  CAS  Google Scholar 

  9. Thomas MC, Fernandez-Villegas A, Carrilero B, Maranon C, Saura D, Noya O, Segovia M, Alarcon de Noya B, Alonso C, Lopez MC. Characterization of an immunodominant antigenic epitope from Trypanosoma cruzi as a biomarker of chronic Chagas’ disease pathology. Clin Vaccine Immunol. 2012;19(2):167–73. https://doi.org/10.1128/CVI.05566-11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Buschiazzo A, Campetella OE, Macina RA, Salceda S, Frasch AC, Sanchez DO. Sequence of the gene for a Trypanosoma cruzi protein antigenic during the chronic phase of human Chagas disease. Mol Biochem Parasitol. 1992;54(1):125–8.

    Article  PubMed  CAS  Google Scholar 

  11. Fernandez-Villegas A, Thomas MC, Carrilero B, Lasso P, Egui A, Murcia L, Segovia M, Alonso C, Lopez MC. A 12-mer repetitive antigenic epitope from Trypanosoma cruzi is a potential marker of therapeutic efficacy in chronic Chagas’ disease. J Antimicrob Chemother. 2016;71(7):2005–9. https://doi.org/10.1093/jac/dkw090.

    Article  PubMed  CAS  Google Scholar 

  12. Lopez L, Arai K, Gimenez E, Jimenez M, Pascuzo C, Rodriguez-Bonfante C, Bonfante-Cabarcas R (2006) [C-reactive protein and interleukin-6 serum levels increase as Chagas disease progresses towards cardiac failure]. Rev Esp Cardiol 59 (1):50-56

    Google Scholar 

  13. Egui A, Thomas MC, Fernandez-Villegas A, Perez-Anton E, Gomez I, Carrilero B, Del Pozo A, Ceballos M, Andres-Leon E, Lopez-Ruz MA, Gainza E, Oquinena E, Segovia M, Lopez MC. A parasite biomarker set for evaluating benznidazole treatment efficacy in patients with chronic asymptomatic Trypanosoma cruzi infection. Antimicrob Agents Chemother. 2019;63(10) https://doi.org/10.1128/AAC.02436-18.

  14. Moretti E, Cervetta L, Basso B, Castro I, Santamarina N. [Chronic Chagas’ disease: effects of treatment nn the levels of antibodies to crude and partially purified Trypanosoma cruzi antigens]. Bol Chil Parasitol 1998;53(1–2):3–9

    Google Scholar 

  15. Krautz GM, Galvao LM, Cancado JR, Guevara-Espinoza A, Ouaissi A, Krettli AU. Use of a 24-kilodalton Trypanosoma cruzi recombinant protein to monitor cure of human Chagas’ disease. J Clin Microbiol. 1995;33(8):2086–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Fabbro DL, Olivera V, Bizai ML, Denner S, Diez C, Marcipar I, Streiger M, Arias E, del Barco M, Mendicino D, Bottasso O. Humoral immune response against P2beta from Trypanosoma cruzi in persons with chronic Chagas disease: its relationship with treatment against parasites and myocardial damage. Am J Trop Med Hyg. 2011;84(4):575–80. https://doi.org/10.4269/ajtmh.2011.10-0261.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas’ disease. Am J Trop Med Hyg. 1998;59(4):526–9.

    Article  PubMed  CAS  Google Scholar 

  18. Fabbro D, Velazquez E, Bizai ML, Denner S, Olivera V, Arias E, Pravia C, Ruiz AM. Evaluation of the ELISA-F29 test as an early marker of therapeutic efficacy in adults with chronic Chagas disease. Rev Inst Med Trop Sao Paulo. 2013;55(3) https://doi.org/10.1590/S0036-46652013000300005.

  19. Sanchez Negrette O, Sanchez Valdez FJ, Lacunza CD, Garcia Bustos MF, Mora MC, Uncos AD, Basombrio MA. Serological evaluation of specific-antibody levels in patients treated for chronic Chagas’ disease. Clin Vaccine Immunol. 2008;15(2):297–302. https://doi.org/10.1128/CVI.00106-07.

    Article  PubMed  CAS  Google Scholar 

  20. Torrico F, Gascon J, Ortiz L, Alonso-Vega C, Pinazo MJ, Schijman A, Almeida IC, Alves F, Strub-Wourgaft N, Ribeiro I, Group ES. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. Lancet Infect Dis. 2018;18(4):419–30. https://doi.org/10.1016/S1473-3099(17)30538-8.

    Article  PubMed  CAS  Google Scholar 

  21. Laucella SA, de Titto EH, Segura EL. Epitopes common to Trypanosoma cruzi and mammalian tissues are recognized by sera from Chagas’ disease patients: prognosis value in Chagas disease. Acta Trop. 1996;62(3):151–62.

    Article  PubMed  CAS  Google Scholar 

  22. Vercosa AF, Lorena VM, Carvalho CL, Melo MF, Cavalcanti MG, Silva ED, Ferreira AG, Pereira VR, Souza WV, Gomes YM. Chagas’ disease: IgG isotypes against cytoplasmic (CRA) and flagellar (FRA) recombinant repetitive antigens of Trypanosoma cruzi in chronic Chagasic patients. J Clin Lab Anal. 2007;21(5):271–6. https://doi.org/10.1002/jcla.20186.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Vasconcelos RH, Amaral FN, Cavalcanti MG, Silva ED, Ferreira AG, Morais CN, Gomes YM. Increased levels of IgA antibodies against CRA and FRA recombinant antigens of Trypanosoma cruzi differentiate digestive forms of Chagas disease. Hum Immunol. 2010;71(10):964–7. https://doi.org/10.1016/j.humimm.2010.07.004.

    Article  PubMed  CAS  Google Scholar 

  24. Junqueira C, Caetano B, Bartholomeu DC, Melo MB, Ropert C, Rodrigues MM, Gazzinelli RT. The endless race between Trypanosoma cruzi and host immunity: lessons for and beyond Chagas disease. Expert Rev Mol Med. 2010;12:e29. https://doi.org/10.1017/S1462399410001560.

    Article  PubMed  CAS  Google Scholar 

  25. Tarleton RL. Depletion of CD8+ T cells increases susceptibility and reverses vaccine-induced immunity in mice infected with Trypanosoma cruzi. J Immunol. 1990;144(2):717–24.

    PubMed  CAS  Google Scholar 

  26. Tarleton RL, Grusby MJ, Postan M, Glimcher LH. Trypanosoma cruzi infection in MHC-deficient mice: further evidence for the role of both class I- and class II-restricted T cells in immune resistance and disease. Int Immunol. 1996;8(1):13–22.

    Article  PubMed  CAS  Google Scholar 

  27. Tarleton RL, Koller BH, Latour A, Postan M. Susceptibility of beta 2-microglobulin-deficient mice to Trypanosoma cruzi infection. Nature. 1992;356(6367):338–40. https://doi.org/10.1038/356338a0.

    Article  PubMed  CAS  Google Scholar 

  28. Tarleton RL, Sun J, Zhang L, Postan M. Depletion of T-cell subpopulations results in exacerbation of myocarditis and parasitism in experimental Chagas’ disease. Infect Immun. 1994;62(5):1820–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Gromme M, Neefjes J. Antigen degradation or presentation by MHC class I molecules via classical and non-classical pathways. Mol Immunol. 2002;39(3-4):181–202.

    Article  PubMed  CAS  Google Scholar 

  30. Martin D, Tarleton R. Generation, specificity, and function of CD8+ T cells in Trypanosoma cruzi infection. Immunol Rev. 2004;201:304–17. https://doi.org/10.1111/j.0105-2896.2004.00183.x.

    Article  PubMed  CAS  Google Scholar 

  31. Yewdell JW, Reits E, Neefjes J. Making sense of mass destruction: quantitating MHC class I antigen presentation. Nat Rev Immunol. 2003;3(12):952–61. https://doi.org/10.1038/nri1250.

    Article  PubMed  CAS  Google Scholar 

  32. Cox MA, Harrington LE, Zajac AJ. Cytokines and the inception of CD8 T cell responses. Trends Immunol. 2011;32(4):180–6. https://doi.org/10.1016/j.it.2011.01.004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012;12(11):749–61. https://doi.org/10.1038/nri3307.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Tosello Boari J, Araujo Furlan CL, Fiocca Vernengo F, Rodriguez C, Ramello MC, Amezcua Vesely MC, Gorosito Serran M, Nunez NG, Richer W, Piaggio E, Montes CL, Gruppi A, Acosta Rodriguez EV. IL-17RA-signaling modulates CD8+ T cell survival and exhaustion during Trypanosoma cruzi infection. Front Immunol. 2018;9:2347. https://doi.org/10.3389/fimmu.2018.02347.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Higuchi Mde L, Benvenuti LA, Martins Reis M, Metzger M. Pathophysiology of the heart in Chagas’ disease: current status and new developments. Cardiovasc Res. 2003;60(1):96–107.

    Article  PubMed  Google Scholar 

  36. Martin DL, Weatherly DB, Laucella SA, Cabinian MA, Crim MT, Sullivan S, Heiges M, Craven SH, Rosenberg CS, Collins MH, Sette A, Postan M, Tarleton RL. CD8+ T-Cell responses to Trypanosoma cruzi are highly focused on strain-variant trans-sialidase epitopes. PLoS Pathog. 2006;2(8):e77. https://doi.org/10.1371/journal.ppat.0020077.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Santos MA, Garg N, Tarleton RL. The identification and molecular characterization of Trypanosoma cruzi amastigote surface protein-1, a member of the trans-sialidase gene super-family. Mol Biochem Parasitol. 1997;86(1):1–11.

    PubMed  CAS  Google Scholar 

  38. Wizel B, Nunes M, Tarleton RL. Identification of Trypanosoma cruzi trans-sialidase family members as targets of protective CD8+ TC1 responses. J Immunol. 1997;159(12):6120–30.

    PubMed  CAS  Google Scholar 

  39. Diez H, Lopez MC, Del Carmen Thomas M, Guzman F, Rosas F, Velazco V, Gonzalez JM, Puerta C. Evaluation of IFN-gamma production by CD8 T lymphocytes in response to the K1 peptide from KMP-11 protein in patients infected with Trypanosoma cruzi. Parasite Immunol. 2006;28(3):101–5. https://doi.org/10.1111/j.1365-3024.2005.00815.x.

    Article  PubMed  CAS  Google Scholar 

  40. Maranon C, Thomas MC, Planelles L, Lopez MC. The immunization of A2/K(b) transgenic mice with the KMP11-HSP70 fusion protein induces CTL response against human cells expressing the T. cruzi KMP11 antigen: identification of A2-restricted epitopes. Mol Immunol. 2001;38(4):279–87.

    Article  PubMed  CAS  Google Scholar 

  41. Engman DM, Krause KH, Blumin JH, Kim KS, Kirchhoff LV, Donelson JE. A novel flagellar Ca2+-binding protein in trypanosomes. J Biol Chem. 1989;264(31):18627–31.

    PubMed  CAS  Google Scholar 

  42. Garcia F, Sepulveda P, Liegeard P, Gregoire J, Hermann E, Lemonnier F, Langlade-Demoyen P, Hontebeyrie M, Lone YC. Identification of HLA-A*0201-restricted cytotoxic T-cell epitopes of Trypanosoma cruzi TcP2beta protein in HLA-transgenic mice and patients. Microbes Infect. 2003;5(5):351–9.

    Article  PubMed  CAS  Google Scholar 

  43. Fonseca SG, Moins-Teisserenc H, Clave E, Ianni B, Nunes VL, Mady C, Iwai LK, Sette A, Sidney J, Marin ML, Goldberg AC, Guilherme L, Charron D, Toubert A, Kalil J, Cunha-Neto E. Identification of multiple HLA-A*0201-restricted cruzipain and FL-160 CD8+ epitopes recognized by T cells from chronically Trypanosoma cruzi-infected patients. Microbes Infect. 2005;7(4):688–97. https://doi.org/10.1016/j.micinf.2005.01.001.

    Article  PubMed  CAS  Google Scholar 

  44. Maranon C, Egui A, Carrilero B, Thomas MC, Pinazo MJ, Gascon J, Segovia M, Lopez MC. Identification of HLA-A *02:01-restricted CTL epitopes in Trypanosoma cruzi heat shock protein-70 recognized by Chagas disease patients. Microbes Infect. 2011;13(12-13):1025–32. https://doi.org/10.1016/j.micinf.2011.05.010.

    Article  PubMed  CAS  Google Scholar 

  45. Egui A, Thomas MC, Morell M, Maranon C, Carrilero B, Segovia M, Puerta CJ, Pinazo MJ, Rosas F, Gascon J, Lopez MC. Trypanosoma cruzi paraflagellar rod proteins 2 and 3 contain immunodominant CD8(+) T-cell epitopes that are recognized by cytotoxic T cells from Chagas disease patients. Mol Immunol. 2012;52(3-4):289–98. https://doi.org/10.1016/j.molimm.2012.05.021.

    Article  PubMed  CAS  Google Scholar 

  46. Egui A, Thomas MC, Carrilero B, Segovia M, Alonso C, Maranon C, Lopez MC. Differential phenotypic and functional profiles of TcCA-2 -specific cytotoxic CD8+ T cells in the asymptomatic versus cardiac phase in Chagasic patients. PLoS One. 2015;10(3):e0122115. https://doi.org/10.1371/journal.pone.0122115.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Rosenberg CS, Martin DL, Tarleton RL. CD8+ T cells specific for immunodominant trans-sialidase epitopes contribute to control of Trypanosoma cruzi infection but are not required for resistance. J Immunol. 2010;185(1):560–8. https://doi.org/10.4049/jimmunol.1000432.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Lasso P, Mesa D, Cuellar A, Guzman F, Bolanos N, Rosas F, Velasco V, Thomas MC, Lopez MC, Gonzalez JM, Puerta CJ. Frequency of specific CD8+ T cells for a promiscuous epitope derived from Trypanosoma cruzi KMP-11 protein in chagasic patients. Parasite Immunol. 2010;32(7):494–502. https://doi.org/10.1111/j.1365-3024.2010.01206.x.

    Article  PubMed  CAS  Google Scholar 

  49. Lasso P, Beltran L, Guzman F, Rosas F, Thomas MC, Lopez MC, Gonzalez JM, Cuellar A, Puerta CJ. Promiscuous recognition of a Trypanosoma cruzi CD8+ T cell epitope among HLA-A2, HLA-A24 and HLA-A1 supertypes in chagasic patients. PLoS One. 2016;11(3):e0150996. https://doi.org/10.1371/journal.pone.0150996.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Alvarez MG, Postan M, Weatherly DB, Albareda MC, Sidney J, Sette A, Olivera C, Armenti AH, Tarleton RL, Laucella SA. HLA Class I-T cell epitopes from trans-sialidase proteins reveal functionally distinct subsets of CD8+ T cells in chronic Chagas disease. PLoS Negl Trop Dis. 2008;2(9):e288. https://doi.org/10.1371/journal.pntd.0000288.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Kumar S, Tarleton RL. Antigen-specific Th1 but not Th2 cells provide protection from lethal Trypanosoma cruzi infection in mice. J Immunol. 2001;166(7):4596–603.

    Article  PubMed  CAS  Google Scholar 

  52. Albareda MC, Laucella SA, Alvarez MG, Armenti AH, Bertochi G, Tarleton RL, Postan M. Trypanosoma cruzi modulates the profile of memory CD8+ T cells in chronic Chagas’ disease patients. Int Immunol. 2006;18(3):465–71. https://doi.org/10.1093/intimm/dxh387.

    Article  PubMed  CAS  Google Scholar 

  53. Laucella SA, Postan M, Martin D, Hubby Fralish B, Albareda MC, Alvarez MG, Lococo B, Barbieri G, Viotti RJ, Tarleton RL. Frequency of interferon- gamma -producing T cells specific for Trypanosoma cruzi inversely correlates with disease severity in chronic human Chagas disease. J Infect Dis. 2004;189(5):909–18. https://doi.org/10.1086/381682.

    Article  PubMed  CAS  Google Scholar 

  54. Lasso P, Mateus J, Pavia P, Rosas F, Roa N, Thomas MC, Lopez MC, Gonzalez JM, Puerta CJ, Cuellar A. Inhibitory receptor expression on CD8+ T cells is linked to functional responses against Trypanosoma cruzi antigens in chronic chagasic patients. J Immunol. 2015;195(8):3748–58. https://doi.org/10.4049/jimmunol.1500459.

    Article  PubMed  CAS  Google Scholar 

  55. Mateus J, Lasso P, Pavia P, Rosas F, Roa N, Valencia-Hernandez CA, Gonzalez JM, Puerta CJ, Cuellar A. Low frequency of circulating CD8+ T stem cell memory cells in chronic chagasic patients with severe forms of the disease. PLoS Negl Trop Dis. 2015;9(1):e3432. https://doi.org/10.1371/journal.pntd.0003432.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, Wang E, Douek DC, Price DA, June CH, Marincola FM, Roederer M, Restifo NP. A human memory T cell subset with stem cell-like properties. Nat Med. 2011;17(10):1290–7. https://doi.org/10.1038/nm.2446.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492–9.

    Article  PubMed  CAS  Google Scholar 

  58. Bustamante JM, Bixby LM, Tarleton RL. Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease. Nat Med. 2008;14(5):542–50. https://doi.org/10.1038/nm1744.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Perez-Mazliah DE, Alvarez MG, Cooley G, Lococo BE, Bertocchi G, Petti M, Albareda MC, Armenti AH, Tarleton RL, Laucella SA, Viotti R. Sequential combined treatment with allopurinol and benznidazole in the chronic phase of Trypanosoma cruzi infection: a pilot study. J Antimicrob Chemother. 2013;68(2):424–37. https://doi.org/10.1093/jac/dks390.

    Article  PubMed  CAS  Google Scholar 

  60. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445–89. https://doi.org/10.1146/annurev-immunol-030409-101212.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature. 2003;421(6925):852–6. https://doi.org/10.1038/nature01441.

    Article  PubMed  CAS  Google Scholar 

  62. Kalams SA, Walker BD. The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J Exp Med. 1998;188(12):2199–204.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Takeuchi A, Saito T. CD4 CTL, a cytotoxic subset of CD4(+) T cells, their differentiation and function. Front Immunol. 2017;8:194. https://doi.org/10.3389/fimmu.2017.00194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Belkaid Y, Tarbell K. Regulatory T cells in the control of host-microorganism interactions (*). Annu Rev Immunol. 2009;27:551–89. https://doi.org/10.1146/annurev.immunol.021908.132723.

    Article  PubMed  CAS  Google Scholar 

  65. de Freitas VL, da Silva SC, Sartori AM, Bezerra RC, Westphalen EV, Molina TD, Teixeira AR, Ibrahim KY, Shikanai-Yasuda MA. Real-time PCR in HIV/Trypanosoma cruzi coinfection with and without Chagas disease reactivation: association with HIV viral load and CD4 level. PLoS Negl Trop Dis. 2011;5(8):e1277. https://doi.org/10.1371/journal.pntd.0001277.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Sanoja C, Carbajosa S, Fresno M, Girones N. Analysis of the dynamics of infiltrating CD4(+) T cell subsets in the heart during experimental Trypanosoma cruzi infection. PLoS One. 2013;8(6):e65820. https://doi.org/10.1371/journal.pone.0065820.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Rodrigues MM, Ribeirao M, Boscardin SB. CD4 Th1 but not Th2 clones efficiently activate macrophages to eliminate Trypanosoma cruzi through a nitric oxide dependent mechanism. Immunol Lett. 2000;73(1):43–50.

    Article  PubMed  CAS  Google Scholar 

  68. Albareda MC, Olivera GC, Laucella SA, Alvarez MG, Fernandez ER, Lococo B, Viotti R, Tarleton RL, Postan M. Chronic human infection with Trypanosoma cruzi drives CD4+ T cells to immune senescence. J Immunol. 2009;183(6):4103–8. https://doi.org/10.4049/jimmunol.0900852.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Cuellar A, Rojas F, Bolanos N, Diez H, Del Carmen Thomas M, Rosas F, Velasco V, Lopez MC, Gonzalez JM, Puerta C. Natural CD4(+) T-cell responses against Trypanosoma cruzi KMP-11 protein in chronic chagasic patients. Immunol Cell Biol. 2009;87(2):149–53. https://doi.org/10.1038/icb.2008.76.

    Article  PubMed  CAS  Google Scholar 

  70. 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):1185–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Keesen TS, Gomes JA, Fares RC, de Araujo FF, Ferreira KS, Chaves AT, Rocha MO, Correa-Oliveira R. Characterization of CD4(+) cytotoxic lymphocytes and apoptosis markers induced by Trypanossoma cruzi infection. Scand J Immunol. 2012;76(3):311–9. https://doi.org/10.1111/j.1365-3083.2012.02730.x.

    Article  PubMed  CAS  Google Scholar 

  72. Alvarez MG, Bertocchi GL, Cooley G, Albareda MC, Viotti R, Perez-Mazliah DE, Lococo B, Castro Eiro M, Laucella SA, Tarleton RL. Treatment success in Trypanosoma cruzi infection is predicted by early changes in serially monitored parasite-specific T and B cell responses. PLoS Negl Trop Dis. 2016;10(4):e0004657. https://doi.org/10.1371/journal.pntd.0004657.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Vallejo A, Monge-Maillo B, Gutierrez C, Norman FF, Lopez-Velez R, Perez-Molina JA. Changes in the immune response after treatment with benznidazole versus no treatment in patients with chronic indeterminate Chagas disease. Acta Trop. 2016;164:117–24. https://doi.org/10.1016/j.actatropica.2016.09.010.

    Article  PubMed  CAS  Google Scholar 

  74. Guedes PM, Gutierrez FR, Silva GK, Dellalibera-Joviliano R, Rodrigues GJ, Bendhack LM, Rassi A Jr, Rassi A, Schmidt A, Maciel BC, Marin Neto JA, Silva JS. Deficient regulatory T cell activity and low frequency of IL-17-producing T cells correlate with the extent of cardiomyopathy in human Chagas’ disease. PLoS Negl Trop Dis. 2012;6(4):e1630. https://doi.org/10.1371/journal.pntd.0001630.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Magalhaes LM, Villani FN, Nunes Mdo C, Gollob KJ, Rocha MO, Dutra WO. High interleukin 17 expression is correlated with better cardiac function in human Chagas disease. J Infect Dis. 2013;207(4):661–5. https://doi.org/10.1093/infdis/jis724.

    Article  PubMed  CAS  Google Scholar 

  76. Crawford A, Wherry EJ. The diversity of costimulatory and inhibitory receptor pathways and the regulation of antiviral T cell responses. Curr Opin Immunol. 2009;21(2):179–86. https://doi.org/10.1016/j.coi.2009.01.010.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Morou A, Palmer BE, Kaufmann DE. Distinctive features of CD4+ T cell dysfunction in chronic viral infections. Curr Opin HIV AIDS. 2014;9(5):446–51. https://doi.org/10.1097/COH.0000000000000094.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Arguello RJ, Albareda MC, Alvarez MG, Bertocchi G, Armenti AH, Vigliano C, Meckert PC, Tarleton RL, Laucella SA. Inhibitory receptors are expressed by Trypanosoma cruzi-specific effector T cells and in hearts of subjects with chronic Chagas disease. PLoS One. 2012;7(5):e35966. https://doi.org/10.1371/journal.pone.0035966.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Arguello RJ, Vigliano C, Cabeza-Meckert P, Viotti R, Garelli F, Favaloro LE, Favaloro RR, Laguens R, Laucella SA. Presence of antigen-experienced T cells with low grade of differentiation and proliferative potential in chronic Chagas disease myocarditis. PLoS Negl Trop Dis. 2014;8(8):e2989. https://doi.org/10.1371/journal.pntd.0002989.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Chaves AT, de Assis Silva Gomes Estanislau J, Fiuza JA, Carvalho AT, Ferreira KS, Fares RC, Guimaraes PH, de Souza Fagundes EM, Morato MJ, Fujiwara RT, da Costa Rocha MO, Correa-Oliveira R. Immunoregulatory mechanisms in Chagas disease: modulation of apoptosis in T-cell mediated immune responses. BMC Infect Dis. 2016;16:191. https://doi.org/10.1186/s12879-016-1523-1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Overgaard NH, Jung JW, Steptoe RJ, Wells JW. CD4+/CD8+ double-positive T cells: more than just a developmental stage? J Leukoc Biol. 2015;97(1):31–8. https://doi.org/10.1189/jlb.1RU0814-382.

    Article  PubMed  CAS  Google Scholar 

  82. Parel Y, Chizzolini C. CD4+ CD8+ double positive (DP) T cells in health and disease. Autoimmun Rev. 2004;3(3):215–20. https://doi.org/10.1016/j.autrev.2003.09.001.

    Article  PubMed  Google Scholar 

  83. Clenet ML, Gagnon F, Moratalla AC, Viel EC, Arbour N. Peripheral human CD4+CD8+ T lymphocytes exhibit a memory phenotype and enhanced responses to IL-2, IL-7 and IL-15. Sci Rep. 2017;7(1):11612. https://doi.org/10.1038/s41598-017-11926-2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Giraldo NA, Bolanos NI, Cuellar A, Guzman F, Uribe AM, Bedoya A, Olaya N, Cucunuba ZM, Roa N, Rosas F, Velasco V, Puerta CJ, Gonzalez JM. Increased CD4+/CD8+ double-positive T cells in chronic Chagasic patients. PLoS Negl Trop Dis. 2011;5(8):e1294. https://doi.org/10.1371/journal.pntd.0001294.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Morrot A, Terra-Granado E, Perez AR, Silva-Barbosa SD, Milicevic NM, Farias-de-Oliveira DA, Berbert LR, De Meis J, Takiya CM, Beloscar J, Wang X, Kont V, Peterson P, Bottasso O, Savino W. Chagasic thymic atrophy does not affect negative selection but results in the export of activated CD4+CD8+ T cells in severe forms of human disease. PLoS Negl Trop Dis. 2011;5(8):e1268. https://doi.org/10.1371/journal.pntd.0001268.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Perez-Anton E, Egui A, Thomas MC, Puerta CJ, Gonzalez JM, Cuellar A, Segovia M, Lopez MC. Impact of benznidazole treatment on the functional response of Trypanosoma cruzi antigen-specific CD4+CD8+ T cells in chronic Chagas disease patients. PLoS Negl Trop Dis. 2018;12(5):e0006480. https://doi.org/10.1371/journal.pntd.0006480.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Perez AR, Morrot A, Berbert LR, Terra-Granado E, Savino W. Extrathymic CD4+CD8+ lymphocytes in Chagas disease: possible relationship with an immunoendocrine imbalance. Ann N Y Acad Sci. 2012;1262:27–36. https://doi.org/10.1111/j.1749-6632.2012.06627.x.

    Article  PubMed  CAS  Google Scholar 

  88. Zloza A, Al-Harthi L. Multiple populations of T lymphocytes are distinguished by the level of CD4 and CD8 coexpression and require individual consideration. J Leukoc Biol. 2006;79(1):4–6. https://doi.org/10.1189/jlb.0805455.

    Article  PubMed  CAS  Google Scholar 

  89. Sullivan YB, Landay AL, Zack JA, Kitchen SG, Al-Harthi L. Upregulation of CD4 on CD8+ T cells: CD4dimCD8bright T cells constitute an activated phenotype of CD8+ T cells. Immunology. 2001;103(3):270–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Instituto de Parasitología y Biomedicina López Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain

    M. Carmen Thomas, Adriana Egui, Elena Pérez-Antón, Inmaculada Gómez & Manuel C. López

  2. NHEPACHA network, Barcelona, Spain

    M. Carmen Thomas & Manuel C. López

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Thomas, M.C., Egui, A., Pérez-Antón, E., Gómez, I., López, M.C. (2020). Challenges in Response to Treatment Evaluation and Progression of the Disease. In: Pinazo Delgado, MJ., Gascón, J. (eds) Chagas Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-44054-1_11

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