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Medical Microbiology and Immunology

, Volume 205, Issue 4, pp 353–369 | Cite as

American tegumentary leishmaniasis: T-cell differentiation profile of cutaneous and mucosal forms—co-infection with Trypanosoma cruzi

  • Cecilia Parodi
  • María F. García Bustos
  • Alejandra Barrio
  • Federico Ramos
  • Ana G. González Prieto
  • María C. Mora
  • Patricia Baré
  • Miguel A. Basombrío
  • María M. de Elizalde de Bracco
Original Investigation

Abstract

American tegumentary leishmaniasis displays two main clinical forms: cutaneous (CL) and mucosal (ML). ML is more resistant to treatment and displays a more severe and longer evolution. Since both forms are caused by the same Leishmania species, the immunological response of the host may be an important factor determining the evolution of the disease. Herein, we analyzed the differentiation and memory profile of peripheral CD4+ and CD8+ T lymphocytes of patients with CL and ML and their LeishmaniaT. cruzi co-infected counterparts. We measured the expression of CD27, CD28, CD45RO, CD127, PD-1 and CD57, together with interferon-γ and perforin. A highly differentiated phenotype was reflected on both T subsets in ML and preferentially on CD8+ T cells in CL. A positive trend toward a higher T differentiation profile was found in T. cruzi-infected CL and ML patients as compared with Leishmania single infections. Association between CD8+ T-cell differentiation and illness duration was found within the first year of infection, with progressive increase of highly differentiated markers over time. Follow-up of patients with good response to therapy showed predominance of early differentiated CD8+ T cells and decrease of highly differentiated cells, while patients with frequent relapses presented the opposite pattern. CD8+ T cells showed the most striking changes in their phenotype during leishmaniasis. Patients with long-term infections showed the highest differentiated degree implying a relation between T differentiation and parasite persistence. Distinct patterns of CD8+ T differentiation during follow-up of different clinical outcomes suggest the usefulness of this analysis in the characterization of Leishmania-infected patients.

Keywords

Cutaneous leishmaniasis Mucosal leishmaniasis Peripheral T lymphocytes Differentiation and memory phenotype LeishmaniaT. cruzi co-infection 

Notes

Acknowledgments

Authors would like to thank Dermatology Service of Hospital Señor del Milagro and Dermatology/Otorhinolaryngology Services of Hospital San Bernardo, Salta, Argentina. We would also like to thank Marta Felippo, Nora Galassi and Norma Riera for bringing their knowledge and help in the flow cytometry acquisition and analyses. We would like to give special thanks to Susana Laucella, for carefully reading and correcting on the entire manuscript.

Funding

This work was supported by grants from Bunge & Born Foundation (FBBEI6/08), Alberto J. Roemmers Foundation, René Barón Foundation and National Agency for Scientific and Technological Promotion (FONCYT-PICT-00983), Argentina.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individuals participants included in the study.

Supplementary material

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Supplementary material 1 (DOCX 14 kb)
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Supplementary material 2 (DOCX 13 kb)
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Supplementary material 3 (DOCX 13 kb)
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Supplementary material 4 (DOCX 15 kb)

References

  1. 1.
    Herwaldt BL (1999) Leishmaniasis. Lancet 354(9185):1191–1199CrossRefPubMedGoogle Scholar
  2. 2.
    Murray HW, Berman JD, Davies CR, Saravia NG (2005) Advances in leishmaniasis. Lancet 366(9496):1561–1577CrossRefPubMedGoogle Scholar
  3. 3.
    Amato VS, Tuon FF, Bacha HA, Neto VA, Nicodemo AC (2008) Mucosal leishmaniasis. Current scenario and prospects for treatment. Acta Trop 105(1):1–9CrossRefPubMedGoogle Scholar
  4. 4.
    David CV, Craft N (2009) Cutaneous and mucocutaneous leishmaniasis. Dermatol Ther 22(6):491–502CrossRefPubMedGoogle Scholar
  5. 5.
    Goto H, Lindoso LA (2010) Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther 8(4):419–433CrossRefPubMedGoogle Scholar
  6. 6.
    Telino E, De Luca PM, Matos DC, Azeredo-Coutinho RB, Meirelles MN, Conceição-Silva F et al (2006) In vitro responses of human peripheral blood mononuclear cells to whole-cell, particulate and soluble extracts of Leishmania promastigotes. Clin Exp Immunol 143(2):338–344CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Macedo AB, Sánchez-Arcila JC, Schubach AO, Mendonça SC, Marins-Dos-Santos A, de Fatima Madeira M et al (2012) Multifunctional CD4+ T cells in patients with American cutaneous leishmaniasis. Clin Exp Immunol 167(3):505–513CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bacellar O, Lessa H, Schriefer A, Machado P, Ribeiro de Jesus A, Dutra WO et al (2002) Up-regulation of Th1-type responses in mucosal leishmaniasis patients. Infect Immun 70(12):6734–6740CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Carvalho LP, Passos S, Schriefer A, Carvalho EM (2012) Protective and pathologic immune responses in human tegumentary leishmaniasis. Front Immunol. doi: 10.3389/fimmu.2012.00301 Google Scholar
  10. 10.
    Chiaramonte MG, Zwirner NW, Caropresi SL, Taranto NJ, Malchiodi EL (1996) Trypanosoma cruzi and Leishmania spp. human mixed infection. Am J Trop Med Hyg 54(3):271–273PubMedGoogle Scholar
  11. 11.
    Frank FM, Fernández MM, Taranto NJ, Cajal SP, Margni RA, Castro E et al (2003) Characterization of human infection by Leishmania spp. in the Northwest of Argentina: immune response, double infection with Trypanosoma cruzi and species of Leishmania involved. Parasitology 126(Pt 1):31–39CrossRefPubMedGoogle Scholar
  12. 12.
    Barrio A, Mora MC, Ramos F, Moreno S, Samson R, Basombrío MA (2007) Use of kDNA-based polymerase chain reaction as a sensitive and differentially diagnostic method of American tegumentary leishmaniasis in disease-endemic areas of northern Argentina. Am J Trop Med Hyg 77(4):636–639PubMedGoogle Scholar
  13. 13.
    Barrio A, García Bustos MF, Mora MC, Parodi C, Ramos F, Moreno S et al (2009) Identificación por PS-PCR de especies de Leishmania y su correlación con características clínicas, epidemiológicas y terapéuticas en Salta, Argentina. Revista Argentina de Salud Pública 1(1):30–33Google Scholar
  14. 14.
    Desjeux P (2004) Leishmaniasis: current situation and new perspectives. Comp Immunol Microbiol Infect Dis 27(5):305–318CrossRefPubMedGoogle Scholar
  15. 15.
    Lanús CE, Piñero JE, González AC, Valladares B, de Grosso ML, Salomón OD (2005) Detection of Leishmania braziliensis in human paraffin-embedded tissues from Tucumán, Argentina by polymerase chain reaction. Mem Inst Oswaldo Cruz 100(2):187–192CrossRefPubMedGoogle Scholar
  16. 16.
    Lanús CE, De Grosso ML, Piñero JE, Valladares B, Salomón OD (2006) Natural infection of Lutzomyia neivai with Leishmania spp. in northwestern Argentina. Acta Trop 98(1):1–5CrossRefGoogle Scholar
  17. 17.
    Salomón OD, Rosa JR, Stein M, Quintana MG, Fernández MS, Visintin AM, Spinelli GR (2008) Phlebotominae (Diptera: Psycodidae) fauna in the Chaco region and Cutaneous Leishmaniasis transmission patterns in Argentina. Mem Inst Oswaldo Cruz 103(6):578–584CrossRefPubMedGoogle Scholar
  18. 18.
    Quintana MG, Fernández MS, Salomón OD (2012) Distribution and abundance of phlebotominae, vectors of leishmaniasis, in Argentina: spatial and temporal analysis at different scales. J Trop Med. doi: 10.1155/2012/652803 Google Scholar
  19. 19.
    Walton BC, Chinel LV, Eguia y Eguia O (1973) Onset of espundia after many years of occult infection with Leishmania braziliensis. Am J Trop Med Hyg 22(6):696–698PubMedGoogle Scholar
  20. 20.
    García Bustos MF, Barrio AB, Parodi Ramoneda CM, Ramos F, Mora MC, Convit J et al (2011) Immunological correlates of cure in the first American cutaneous leishmaniasis patient treated by immunotherapy in Argentina. A case report. Invest Clin 52(4):365–375PubMedGoogle Scholar
  21. 21.
    García Bustos MF, González-Prieto G, Ramos F, Mora MC, Hashiguchi Y, Parodi C et al (2016) Clinical and epidemiological features of leishmaniasis in northwestern-Argentina through a retrospective analysis of recent cases. Acta Trop 154:125–132. doi: 10.1016/j.actatropica.2015.11.008 CrossRefPubMedGoogle Scholar
  22. 22.
    Medeiros AR, Silva WA Jr, Roselino AM (2008) DNA sequencing confirms the involvement of Leishmania (L.) amazonensis in American tegumentary leishmaniasis in the state of São Paulo, Brazil. Clinics 63(4):451–456CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Vega Benedetti AF, Cimino RO, Cajal PS, del Juarez Mdel V, Villalpando CA, Gil JF et al (2013) Performance of different Trypanosoma cruzi antigens in the diagnosis of Chagas disease in patients with American cutaneous leishmaniasis from a co-endemic region in Argentina. Trop Med Int Health 18(9):1103–1109CrossRefPubMedGoogle Scholar
  24. 24.
    Chulay JD, Spencer HC, Mugambi M (1985) Electrocardiographic changes during treatment of leishmaniasis with pentavalent antimony (sodium stibogluconate). Am J Trop Med Hyg 34(4):702–709PubMedGoogle Scholar
  25. 25.
    Lawn SD, Armstrong M, Chilton D, Whitty CJ (2006) Electrocardiographic and biochemical adverse effects of sodium stibogluconate during treatment of cutaneous and mucosal leishmaniasis among returned travellers. Trans R Soc Trop Med Hyg 100(3):264–269CrossRefPubMedGoogle Scholar
  26. 26.
    Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L et al (2002) Memory CD8 + T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8(4):379–385CrossRefPubMedGoogle Scholar
  27. 27.
    Appay V, Rowland-Jones SL (2004) Lessons from the study of T-cell differentiation in persistent human virus infection. Semin Immunol 16(3):205–212CrossRefPubMedGoogle Scholar
  28. 28.
    Albareda MC, Laucella SA, Alvarez MG, Armenti AH, Bertochi G, Tarleton RL et al (2006) Trypanosoma cruzi modulates the profile of memory CD8+ T cells in chronic Chagas’ disease patients. Int Immunol 18(3):465–471CrossRefPubMedGoogle Scholar
  29. 29.
    Albareda MC, Olivera GC, Laucella SA, Alvarez MG, Fernandez ER, Lococo B et al (2009) Chronic human infection with Trypanosoma cruzi drives CD4+ T cells to immune senescence. J Immunol 183(6):4103–4108CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE et al (2006) Expression of the interleukin-7 receptor alpha chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J Virol 80(7):3532–3540CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Blattman JN, Wherry EJ, Ha SJ, van der Most RG, Ahmed R (2009) Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection. J Virol 83(9):4386–4394CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Colle JH, Moreau JL, Fontanet A, Lambotte O, Joussemet M, Jacod S et al (2006) Regulatory dysfunction of the interleukin-7 receptor in CD4 and CD8 lymphocytes from HIV-infected patients–effects of antiretroviral therapy. J Acquir Immune Defic Syndr 42(3):277–285CrossRefPubMedGoogle Scholar
  33. 33.
    Colle JH, Moreau JL, Fontanet A, Lambotte O, Joussemet M, Delfraissy JF et al (2006) CD127 expression and regulation are altered in the memory CD8 T cells of HIV-infected patients–reversal by highly active anti-retroviral therapy (HAART). Clin Exp Immunol 143(3):398–403CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zhang SY, Zhang Z, Fu JL, Kang FB, Xu XS, Nie WM et al (2009) Progressive CD127 down-regulation correlates with increased apoptosis of CD8 T cells during chronic HIV-1 infection. Eur J Immunol 39(5):1425–1434CrossRefPubMedGoogle Scholar
  35. 35.
    Joshi T, Rodriguez S, Perovic V, Cockburn IA, Stäger S (2009) B7-H1 blockade increases survival of dysfunctional CD8(+) T cells and confers protection against Leishmania donovani infections. PLoS Pathog. doi: 10.1371/journal.ppat.1000431 Google Scholar
  36. 36.
    Wang EC, Borysiewicz LK (1995) The role of CD8+, CD57+ cells in human cytomegalovirus and other viral infections. Scand J Infect Dis Suppl 99:69–77PubMedGoogle Scholar
  37. 37.
    Rowbottom AW, Garland RJ, Lepper MW, Kaneria SS, Goulden NJ, Oakhill A et al (2000) Functional analysis of the CD8+CD57+ cell population in normal healthy individuals and matched unrelated T-cell-depleted bone marrow transplant recipients. Br J Haematol 110(2):315–321CrossRefPubMedGoogle Scholar
  38. 38.
    Sze DM, Giesajtis G, Brown RD, Raitakari M, Gibson J, Ho J et al (2001) Clonal cytotoxic T cells are expanded in myeloma and reside in the CD8(+)CD57(+)CD28(−) compartment. Blood 98(9):2817–2827CrossRefPubMedGoogle Scholar
  39. 39.
    Faria DR, Gollob KJ, Barbosa J Jr, Schriefer A, Machado PR, Lessa H et al (2005) Decreased in situ expression of interleukin-10 receptor is correlated with the exacerbated inflammatory and cytotoxic responses observed in mucosal leishmaniasis. Infect Immun 73(12):7853–7859CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Carvalho LP, Passos S, Bacellar O, Lessa M, Almeida RP, Magalhães A et al (2007) Differential immune regulation of activated T cells between cutaneous and mucosal leishmaniasis as a model for pathogenesis. Parasite Immunol 29(5):251–258CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Carvalho EM, Johnson WD, Barreto E, Marsden PD, Costa JL, Reed S et al (1985) Cell mediated immunity in American cutaneous and mucosal leishmaniasis. J Immunol 135(6):4144–4148PubMedGoogle Scholar
  42. 42.
    Ribeiro-de-Jesus A, Almeida RP, Lessa H, Bacellar O, Carvalho EM (1998) Cytokine profile and pathology in human leishmaniasis. Braz J Méd Biol Res 31(1):143–148CrossRefPubMedGoogle Scholar
  43. 43.
    Hailu A, van Vaharle D, Knol GJ, Berhe N, Miedema F, Kager PA (2005) T cell subset and cytokine profiles in human visceral leishmaniasis during active and asymptomatic or sub-clinical infection with Leishmania donovani. Clin Immunol 117(2):182–191CrossRefPubMedGoogle Scholar
  44. 44.
    Keshavarz Valian H, Nateghi Rostami M, Tasbihi M, Miramin Mohammadi A, Eskandari SE, Sarrafnejad A et al (2013) CCR7+ central and CCR7 effector memory CD4+ T cells in human cutaneous leishmaniasis. J Clin Immunol 33(1):220–234CrossRefPubMedGoogle Scholar
  45. 45.
    Khamesipour A, Nateghi Rostami M, Tasbihi M, Miramin Mohammadi A, Shahrestani T, Sarrafnejad A et al (2012) Phenotyping of circulating CD8+ T cell subsets in human cutaneous leishmaniasis. Microbes Infect 14(9):702–711CrossRefPubMedGoogle Scholar
  46. 46.
    Bottrel RL, Dutra WO, Martins FA, Gontijo B, Carvalho E, Barral-Netto M et al (2001) Flow cytometric determination of cellular sources and frequencies of key cytokine-producing lymphocytes directed against recombinant LACK and soluble Leishmania antigen in human cutaneous leishmaniasis. Infect Immun 69(5):3232–3239CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Rodriguez-Pinto D, Navas A, Blanco VM, Ramírez L, Garcerant D, Cruz A et al (2012) Regulatory T cells in the pathogenesis and healing of chronic human dermal leishmaniasis caused by Leishmania (Viannia) species. PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0001627 PubMedPubMedCentralGoogle Scholar
  48. 48.
    Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, Rosen HR (2007) Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction. J Virol 81(17):9249–9258CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Burgers WA, Riou C, Mlotshwa M, Maenetje P, de Assis Rosa D, Brenchley J et al (2009) CAPRISA 002 Acute Infection Study Team. Association of HIV-specific and total CD8+ T memory phenotypes in subtype C HIV-1 infection with viral set point. J Immunol 182(8):4751–4761CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Singh S, Sivakumar R (2003) Recent advances in the diagnosis of leishmaniasis. J Postgrad Med 49(1):55–60CrossRefPubMedGoogle Scholar
  51. 51.
    Oliveira JG, Novais FO, de Oliveira CI, da Cruz AC, Jr Campos LF, da Rocha AV et al (2005) Polymerase chain reaction (PCR) is highly sensitive for diagnosis of mucosal leishmaniasis. Acta Trop 94(1):55–59CrossRefPubMedGoogle Scholar
  52. 52.
    Schubach A, Cuzzi-Maya T, Oliveira AV, Sartori A, de Oliveira-Neto MP, Mattos MS et al (2001) Leishmanial antigens in the diagnosis of active lesions and ancient scars of American tegumentary leishmaniasis patients. Mem Inst Oswaldo Cruz 96(7):987–996CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Cecilia Parodi
    • 1
    • 2
  • María F. García Bustos
    • 1
  • Alejandra Barrio
    • 3
  • Federico Ramos
    • 1
  • Ana G. González Prieto
    • 3
  • María C. Mora
    • 1
  • Patricia Baré
    • 2
  • Miguel A. Basombrío
    • 1
  • María M. de Elizalde de Bracco
    • 2
  1. 1.Instituto de Patología Experimental-CONICETUniversidad Nacional de SaltaSaltaArgentina
  2. 2.Laboratorio de Inmunología, Instituto de Medicina Experimental-CONICETAcademia Nacional de MedicinaBuenos AiresArgentina
  3. 3.Cátedra de Microbiología, Facultad de Ciencias de la SaludUniversidad Nacional de SaltaSaltaArgentina

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