Volume 98, Issue 3
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Manifestations of infection range from asymptomatic to symptomatic visceral leishmaniasis (VL). People with symptomatic VL (sVL) have suppressed immune responses against Leishmania antigens that are reversed after clinical cure. The intradermal leishmanin skin test (LST) is negative during sVL, but it becomes positive after treatment. The aim of this study was to compare T cell responses in individuals with sVL, recovered VL (RecVL), and endemic controls. Endemic controls were household contacts of a VL case and they were grouped by their LST results, either positive (LST+) or negative (LST−). Mononuclear cells were studied ex vivo or after stimulation with soluble Leishmania antigens (SLA); cell surface markers and cytokines were determined. T cells, ex vivo, from individuals with sVL and from LST+ individuals presented a higher activation for CD4 and CD8 cells expressing CD69. However, lymphocytes from sVL stimulated with SLA had lower percentages of CD4 and CD8 cells expressing CD69 and CD8 cells expressing CD25, with no release of interferon-γ or tumor necrosis factor. sVL subjects had lower percentage of memory cells (CD4 CD45RO+), ex vivo, without SLA stimulation than RecVL, LST+, or LST− ( = 0.0022). However, individuals with sVL had fewer regulatory cells after SLA stimulation (CD4 CD25, = 0.04 and CD4 FOXP3+, = 0.02) than RecVL. The decrease in specific memory and activated CD4 and CD8 cells, as in response to Leishmania antigens, could explain, in part, the immune impairment during sVL. Finally, protective T cell responses are long lasting because both RecVL or LST+ individuals maintain a specific protective response to Leishmania years after the primary infection.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Lainson R, Shaw JJ, Silveira FT, Braga RR, , 1987. American visceral leishmaniasis: on the origin of Leishmania (Leishmania) chagasi. Trans R Soc Trop Med Hyg 81: 517. [Google Scholar]
  2. Mauricio IL, Stothard JR, Miles MA, , 2000. The strange case of Leishmania chagasi. Parasitol Today 16: 188189. [Google Scholar]
  3. Evans TG, Teixeira MJ, McAuliffe IT, Vasconcelos I, Vasconcelos AW, Sousa AA, Lima JW, Pearson RD, , 1992. Epidemiology of visceral leishmaniasis in northeast Brazil. J Infect Dis 166: 11241132. [Google Scholar]
  4. Wilson ME, Jeronimo SM, Pearson RD, , 2005. Immunopathogenesis of infection with the visceralizing Leishmania species. Microb Pathog 38: 147160. [Google Scholar]
  5. Caldas AJ, Costa JM, Silva AA, Vinhas V, Barral A, , 2002. Risk factors associated with asymptomatic infection by Leishmania chagasi in north-east Brazil. Trans R Soc Trop Med Hyg 96: 2128. [Google Scholar]
  6. Badaro R, Jones TC, Lorenco R, Cerf BJ, Sampaio D, Carvalho EM, Rocha H, Teixeira R, Johnson WD, Jr, 1986. A prospective study of visceral leishmaniasis in an endemic area of Brazil. J Infect Dis 154: 639649. [Google Scholar]
  7. Costa CH, ., 2002. Asymptomatic human carriers of Leishmania chagasi. Am J Trop Med Hyg 66: 334337. [Google Scholar]
  8. Lima ID, ., 2012. Leishmania infantum chagasi in northeastern Brazil: asymptomatic infection at the urban perimeter. Am J Trop Med Hyg 86: 99107. [Google Scholar]
  9. Carvalho EM, Barral A, Pedral-Sampaio D, Barral-Netto M, Badaro R, Rocha H, Johnson WD, Jr, 1992. Immunologic markers of clinical evolution in children recently infected with Leishmania donovani chagasi. J Infect Dis 165: 535540. [Google Scholar]
  10. Badaro R, Carvalho EM, Rocha H, Queiroz AC, Jones TC, , 1986. Leishmania donovani: an opportunistic microbe associated with progressive disease in three immunocompromised patients. Lancet 1: 647649. [Google Scholar]
  11. Jeronimo SM, Teixeira MJ, Sousa A, Thielking P, Pearson RD, Evans TG, , 2000. Natural history of Leishmania (Leishmania) chagasi infection in northeastern Brazil: long-term follow-up. Clin Infect Dis 30: 608609. [Google Scholar]
  12. Kaye P, Scott P, , 2011. Leishmaniasis: complexity at the host-pathogen interface. Nat Rev Microbiol 9: 604615. [Google Scholar]
  13. Stassen M, ., 2004. Human CD25+ regulatory T cells: two subsets defined by the integrins alpha 4 beta 7 or alpha 4 beta 1 confer distinct suppressive properties upon CD4+ T helper cells. Eur J Immunol 34: 13031311. [Google Scholar]
  14. Fakiola M, ., 2011. Genetic and functional evidence implicating DLL1 as the gene that influences susceptibility to visceral leishmaniasis at chromosome 6q27. J Infect Dis 204: 467477. [Google Scholar]
  15. Mehrotra S, ., 2011. No evidence for association between SLC11A1 and visceral leishmaniasis in India. BMC Med Genet 12: 71. [Google Scholar]
  16. Valenzuela JG, Belkaid Y, Garfield MK, Mendez S, Kamhawi S, Rowton ED, Sacks DL, Ribeiro JM, , 2001. Toward a defined anti-Leishmania vaccine targeting vector antigens: characterization of a protective salivary protein. J Exp Med 194: 331342. [Google Scholar]
  17. Carvalho EM, Bacellar O, Barral A, Badaro R, Johnson WD, Jr, 1989. Antigen-specific immunosuppression in visceral leishmaniasis is cell mediated. J Clin Invest 83: 860864. [Google Scholar]
  18. Carvalho EM, Badaro R, Reed SG, Jones TC, Johnson WD, Jr, 1985. Absence of gamma interferon and interleukin 2 production during active visceral leishmaniasis. J Clin Invest 76: 20662069. [Google Scholar]
  19. Saha S, ., 2007. IL-10- and TGF-beta-mediated susceptibility in kala-azar and post-kala-azar dermal leishmaniasis: the significance of amphotericin B in the control of Leishmania donovani infection in India. J Immunol 179: 55925603. [Google Scholar]
  20. Ansari NA, Kumar R, Gautam S, Nylen S, Singh OP, Sundar S, Sacks D, , 2011. IL-27 and IL-21 are associated with T cell IL-10 responses in human visceral leishmaniasis. J Immunol 186: 39773985. [Google Scholar]
  21. Ansari NA, Saluja S, Salotra P, , 2006. Elevated levels of interferon-gamma, interleukin-10, and interleukin-6 during active disease in Indian kala azar. Clin Immunol 119: 339345. [Google Scholar]
  22. Peruhype-Magalhaes V, ., 2006. Mixed inflammatory/regulatory cytokine profile marked by simultaneous raise of interferon-gamma and interleukin-10 and low frequency of tumour necrosis factor-alpha(+) monocytes are hallmarks of active human visceral Leishmaniasis due to Leishmania chagasi infection. Clin Exp Immunol 146: 124132. [Google Scholar]
  23. Singh OP, Gidwani K, Kumar R, Nylen S, Jones SL, Boelaert M, Sacks D, Sundar S, , 2012. Reassessment of immune correlates in human visceral leishmaniasis as defined by cytokine release in whole blood. Clin Vaccine Immunol 19: 961966. [Google Scholar]
  24. Jordan KA, Hunter CA, , 2010. Regulation of CD8+ T cell responses to infection with parasitic protozoa. Exp Parasitol 126: 318325. [Google Scholar]
  25. Gollob KJ, Antonelli LR, Dutra WO, , 2005. Insights into CD4+ memory T cells following Leishmania infection. Trends Parasitol 21: 347350. [Google Scholar]
  26. Maurya R, Kumar R, Prajapati VK, Manandhar KD, Sacks D, Sundar S, Nylen S, , 2010. Human visceral leishmaniasis is not associated with expansion or accumulation of Foxp3+ CD4 cells in blood or spleen. Parasite Immunol 32: 479483. [Google Scholar]
  27. Pakpour N, Zaph C, Scott P, , 2008. The central memory CD4+ T cell population generated during Leishmania major infection requires IL-12 to produce IFN-gamma. J Immunol 180: 82998305. [Google Scholar]
  28. Polley R, Zubairi S, Kaye PM, , 2005. The fate of heterologous CD4+ T cells during Leishmania donovani infection. Eur J Immunol 35: 498504. [Google Scholar]
  29. Nylen S, Maurya R, Eidsmo L, Manandhar KD, Sundar S, Sacks D, , 2007. Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis. J Exp Med 204: 805817. [Google Scholar]
  30. Rai AK, Thakur CP, Singh A, Seth T, Srivastava SK, Singh P, Mitra DK, , 2012. Regulatory T cells suppress T cell activation at the pathologic site of human visceral leishmaniasis. PLoS One 7: e31551. [Google Scholar]
  31. Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL, , 2002. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420: 502507. [Google Scholar]
  32. Baeten DL, Kuchroo VK, , 2013. How cytokine networks fuel inflammation: interleukin-17 and a tale of two autoimmune diseases. Nat Med 19: 824825. [Google Scholar]
  33. Banerjee A, Bhattacharya P, Joshi AB, Ismail N, Dey R, Nakhasi HL, , 2016. Role of pro-inflammatory cytokine IL-17 in Leishmania pathogenesis and in protective immunity by Leishmania vaccines. Cell Immunol 309: 3741. [Google Scholar]
  34. Jeronimo SM, ., 2007. Genetic predisposition to self-curing infection with the protozoan Leishmania chagasi: a genomewide scan. J Infect Dis 196: 12611269. [Google Scholar]
  35. Jeronimo SM, ., 2004. An emerging peri-urban pattern of infection with Leishmania chagasi, the protozoan causing visceral leishmaniasis in northeast Brazil. Scand J Infect Dis 36: 443449. [Google Scholar]
  36. Braz RF, Nascimento ET, Martins DR, Wilson ME, Pearson RD, Reed SG, Jeronimo SM, , 2002. The sensitivity and specificity of Leishmania chagasi recombinant K39 antigen in the diagnosis of American visceral leishmaniasis and in differentiating active from subclinical infection. Am J Trop Med Hyg 67: 344348. [Google Scholar]
  37. Jose FF, da Silva IM, Araujo MI, Almeida RP, Bacellar O, Carvalho EM, , 2001. Evaluation of the sensitization power of Montenegro skin test. Rev Soc Bras Med Trop 34: 537542. [Google Scholar]
  38. Sokal JE, , 1975. Editorial: measurement of delayed skin-test responses. N Engl J Med 293: 501502. [Google Scholar]
  39. Alvar J, Yactayo S, Bern C, , 2006. Leishmaniasis and poverty. Trends Parasitol 22: 552557. [Google Scholar]
  40. Belo VS, Struchiner CJ, Barbosa DS, Nascimento BW, Horta MA, da Silva ES, Werneck GL, , 2014. Risk factors for adverse prognosis and death in American visceral leishmaniasis: a meta-analysis. PLoS Negl Trop Dis 8: e2982. [Google Scholar]
  41. Kaushal H, Bras-Goncalves R, Negi NS, Lemesre JL, Papierok G, Salotra P, , 2014. Role of CD8(+) T cells in protection against Leishmania donovani infection in healed visceral leishmaniasis individuals. BMC Infect Dis 14: 653. [Google Scholar]
  42. Darrah PA, ., 2007. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 13: 843850. [Google Scholar]
  43. Selvapandiyan A, Dey R, Nylen S, Duncan R, Sacks D, Nakhasi HL, , 2009. Intracellular replication-deficient Leishmania donovani induces long lasting protective immunity against visceral leishmaniasis. J Immunol 183: 18131820. [Google Scholar]
  44. Ferrari C, , 2015. HBV and the immune response. Liver Int 35 (Suppl 1): 121128. [Google Scholar]
  45. Chen LM, Fan XG, Ma J, He B, Jiang YF, , 2017. Molecular mechanisms of HBeAg in persistent HBV infection. Hepatol Int 11: 7986. [Google Scholar]
  46. Carvalho EM, Teixeira RS, Johnson WD, Jr, 1981. Cell-mediated immunity in American visceral leishmaniasis: reversible immunosuppression during acute infection. Infect Immun 33: 498500. [Google Scholar]
  47. Gautam S, Kumar R, Maurya R, Nylen S, Ansari N, Rai M, Sundar S, Sacks D, , 2011. IL-10 neutralization promotes parasite clearance in splenic aspirate cells from patients with visceral leishmaniasis. J Infect Dis 204: 11341137. [Google Scholar]
  48. Hernandez-Ruiz J, Salaiza-Suazo N, Carrada G, Escoto S, Ruiz-Remigio A, Rosenstein Y, Zentella A, Becker I, , 2010. CD8 cells of patients with diffuse cutaneous leishmaniasis display functional exhaustion: the latter is reversed, in vitro, by TLR2 agonists. PLoS Negl Trop Dis 4: e871. [Google Scholar]
  49. Taylor JJ, Mohrs M, Pearce EJ, , 2006. Regulatory T cell responses develop in parallel to Th responses and control the magnitude and phenotype of the Th effector population. J Immunol 176: 58395847. [Google Scholar]
  50. Miles SA, Conrad SM, Alves RG, Jeronimo SM, Mosser DM, , 2005. A role for IgG immune complexes during infection with the intracellular pathogen Leishmania. J Exp Med 201: 747754. [Google Scholar]
  51. Bogdan C, , 2008. Mechanisms and consequences of persistence of intracellular pathogens: leishmaniasis as an example. Cell Microbiol 10: 12211234. [Google Scholar]
  52. Hailu A, van Baarle 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: 182191. [Google Scholar]
  53. Clarencio J, de Oliveira CI, Favali C, Medina O, Caldas A, Costa CH, Costa DL, Brodskyn C, Barral A, Barral-Netto M, , 2009. Could the lower frequency of CD8+CD18+CD45RO+ lymphocytes be biomarkers of human VL? Int Immunol 21: 137144. [Google Scholar]
  54. Antonelli LR, Dutra WO, Almeida RP, Bacellar O, Gollob KJ, , 2004. Antigen specific correlations of cellular immune responses in human leishmaniasis suggests mechanisms for immunoregulation. Clin Exp Immunol 136: 341348. [Google Scholar]
  55. Scott P, , 2005. Immunologic memory in cutaneous leishmaniasis. Cell Microbiol 7: 17071713. [Google Scholar]
  56. Dieckmann D, Plottner H, Dotterweich S, Schuler G, , 2005. Activated CD4+ CD25+ T cells suppress antigen-specific CD4+ and CD8+ T cells but induce a suppressive phenotype only in CD4+ T cells. Immunology 115: 305314. [Google Scholar]
  57. Zaph C, Uzonna J, Beverley SM, Scott P, , 2004. Central memory T cells mediate long-term immunity to Leishmania major in the absence of persistent parasites. Nat Med 10: 11041110. [Google Scholar]

Data & Media loading...

  • Received : 12 Sep 2016
  • Accepted : 21 Aug 2017
  • Published online : 26 Dec 2017

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error