Skip to main content

The Role of the Immune System in Resistance to Infection

  • Chapter
  • First Online:
Drug Resistance in Leishmania Parasites

Abstract

Leishmaniasis is a spectrum of diseases with clinical symptoms ranging in severity from skin lesions to serious disfigurement and fatal systemic infection. The outcome of infection depends on the parasite species as well as host genetic factors and immune competence. In order to develop a successful infection, Leishmania must evade both the innate and adaptive immune responses. Whilst protective immunity has been driven by Th1-type T cell responses, the role of Th2-type cytokines is not entirely clear, although it has been implicated in susceptibility to leishmaniasis. A successful treatment of all the forms of leishmaniasis depends on efficient elimination of parasites by activated macrophages. Paradoxically, Leishmania species have evolved a variety of strategies to evade leishmanicidal mechanisms and survive in macrophages in the phagosome. Interestingly, most infected individuals develop long-lasting protective immunity following primary infection; however, sterile immunity is hardly ever achieved, and parasites are believed to persist asymptomatically in the host. The vast array of immune cells and cytokines involved in the immune response to Leishmania clearly highlights the complexity of the disease and reveals a complicated net of regulatory and counter-regulatory interactions. This chapter outlines our current knowledge of the immune factors implicated in the disease and discusses the role the immune system plays in resistance to infection.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Basu MK, Ray M. Macrophage and Leishmania: an unacceptable coexistence. Crit Rev Microbiol. 2005;31(3):145–54.

    Article  PubMed  CAS  Google Scholar 

  2. Liew FY, Li Y, Millott S. Tumor necrosis factor-alpha synergizes with IFN-gamma in mediating killing of Leishmania major through the induction of nitric oxide. J Immunol. 1990;145(12):4306–10.

    PubMed  CAS  Google Scholar 

  3. Iniesta V, Gomez-Nieto LC, Corraliza I. The inhibition of arginase by N(omega)-hydroxy-l-arginine controls the growth of Leishmania inside macrophages. J Exp Med. 2001;193(6):777–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Wei XQ, Charles IG, Smith A, Ure J, et al. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature. 1995;375(6530):408–11.

    Article  PubMed  CAS  Google Scholar 

  5. Mukbel RM, Patten C Jr, Gibson K, Ghosh M, et al. Macrophage killing of Leishmania amazonensis amastigotes requires both nitric oxide and superoxide. Am J Trop Med Hyg. 2007;76(4):669–75.

    Article  PubMed  CAS  Google Scholar 

  6. Trinchieri G. Interleukin-12: a cytokine at the interface of inflammation and immunity. Adv Immunol. 1998;70:83–243.

    Article  PubMed  CAS  Google Scholar 

  7. Ricardo-Carter C, Favila M, Polando RE, Cotton RN, et al. Leishmania major inhibits IL-12 in macrophages by signalling through CR3 (CD11b/CD18) and down-regulation of ETS-mediated transcription. Parasite Immunol. 2013;35(12):409–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Belkaid Y, Mendez S, Lira R, Kadambi N, et al. A natural model of Leishmania major infection reveals a prolonged “silent” phase of parasite amplification in the skin before the onset of lesion formation and immunity. J Immunol. 2000;165(2):969–77.

    Article  PubMed  CAS  Google Scholar 

  9. Peters NC, Sacks DL. The impact of vector-mediated neutrophil recruitment on cutaneous leishmaniasis. Cell Microbiol. 2009;11(9):1290–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Peters NC, Egen JG, Secundino N, Debrabant A, et al. In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies. Science. 2008;321(5891):970–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Ribeiro-Gomes FL, Peters NC, Debrabant A, Sacks DL. Efficient capture of infected neutrophils by dendritic cells in the skin inhibits the early anti-leishmania response. PLoS Pathog. 2012;8(2):e1002536.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Ribeiro-Gomes FL, Romano A, Lee S, Roffe E, et al. Apoptotic cell clearance of Leishmania major-infected neutrophils by dendritic cells inhibits CD8(+) T-cell priming in vitro by Mer tyrosine kinase-dependent signaling. Cell Death Dis. 2015;6:e2018.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Guimaraes-Costa AB, Nascimento MT, Froment GS, Soares RP, et al. Leishmania amazonensis promastigotes induce and are killed by neutrophil extracellular traps. Proc Natl Acad Sci USA. 2009;106(16):6748–53.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Carlsen ED, Liang Y, Shelite TR, Walker DH, et al. Permissive and protective roles for neutrophils in leishmaniasis. Clin Exp Immunol. 2015;182(2):109–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Hurrell BP, Schuster S, Grun E, Coutaz M, et al. Rapid sequestration of Leishmania mexicana by neutrophils contributes to the development of chronic lesion. PLoS Pathog. 2015;11(5):e1004929.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Reiner SL, Locksley RM. The regulation of immunity to Leishmania major. Annu Rev Immunol. 1995;13:151–77.

    Article  PubMed  CAS  Google Scholar 

  17. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–52.

    Article  PubMed  CAS  Google Scholar 

  18. Von Stebut E. Immunology of cutaneous leishmaniasis: the role of mast cells, phagocytes and dendritic cells for protective immunity. Eur J Dermatol. 2007;17(2):115–22.

    Google Scholar 

  19. Ritter U, Meissner A, Scheidig C, Korner H. CD8 alpha- and Langerin-negative dendritic cells, but not Langerhans cells, act as principal antigen-presenting cells in leishmaniasis. Eur J Immunol. 2004;34(6):1542–50.

    Article  PubMed  CAS  Google Scholar 

  20. Ng LG, Hsu A, Mandell MA, Roediger B, et al. Migratory dermal dendritic cells act as rapid sensors of protozoan parasites. PLoS Pathog. 2008;4(11):e1000222.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Woelbing F, Kostka SL, Moelle K, Belkaid Y, et al. Uptake of Leishmania major by dendritic cells is mediated by Fcgamma receptors and facilitates acquisition of protective immunity. J Exp Med. 2006;203(1):177–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Bajenoff M, Breart B, Huang AY, Qi H, et al. Natural killer cell behavior in lymph nodes revealed by static and real-time imaging. J Exp Med. 2006;203(3):619–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Feijo D, Tiburcio R, Ampuero M, Brodskyn C, et al. Dendritic cells and Leishmania infection: adding layers of complexity to a complex disease. J Immunol Res. 2016;2016:3967436.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Soong L. Modulation of dendritic cell function by Leishmania parasites. J Immunol. 2008;180(7):4355–60.

    Article  PubMed  CAS  Google Scholar 

  25. Gorak PM, Engwerda CR, Kaye PM. Dendritic cells, but not macrophages, produce IL-12 immediately following Leishmania donovani infection. Eur J Immunol. 1998;28(2):687–95.

    Article  PubMed  CAS  Google Scholar 

  26. von Stebut E, Belkaid Y, Jakob T, Sacks DL, et al. Uptake of Leishmania major amastigotes results in activation and interleukin 12 release from murine skin-derived dendritic cells: implications for the initiation of anti-Leishmania immunity. J Exp Med. 1998;188(8):1547–52.

    Article  Google Scholar 

  27. Bennett CL, Misslitz A, Colledge L, Aebischer T, et al. Silent infection of bone marrow-derived dendritic cells by Leishmania mexicana amastigotes. Eur J Immunol. 2001;31(3):876–83.

    Article  PubMed  CAS  Google Scholar 

  28. Xin L, Li K, Soong L. Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes. Mol Immunol. 2008;45(12):3371–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Silveira FT, Lainson R, Gomes CM, Laurenti MD, et al. Reviewing the role of the dendritic Langerhans cells in the immunopathogenesis of American cutaneous leishmaniasis. Trans R Soc Trop Med Hyg. 2008;102(11):1075–80.

    Article  PubMed  Google Scholar 

  30. Belkaid Y, Butcher B, Sacks DL. Analysis of cytokine production by inflammatory mouse macrophages at the single-cell level: selective impairment of IL-12 induction in Leishmania-infected cells. Eur J Immunol. 1998;28(4):1389–400.

    Article  PubMed  CAS  Google Scholar 

  31. Flohe S, Lang T, Moll H. Synthesis, stability, and subcellular distribution of major histocompatibility complex class II molecules in Langerhans cells infected with Leishmania major. Infect Immun. 1997;65(8):3444–50.

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Martinez-Lopez M, Iborra S, Conde-Garrosa R, Sancho D. Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice. Eur J Immunol. 2015;45(1):119–29.

    Article  PubMed  CAS  Google Scholar 

  33. Akbari M, Honma K, Kimura D, Miyakoda M, et al. IRF4 in dendritic cells inhibits IL-12 production and controls Th1 immune responses against Leishmania major. J Immunol. 2014;192(5):2271–9.

    Article  PubMed  CAS  Google Scholar 

  34. Bogdan C, Rollinghoff M, Diefenbach A. The role of nitric oxide in innate immunity. Immunol Rev. 2000;173:17–26.

    Article  PubMed  CAS  Google Scholar 

  35. Scott P. The role of TH1 and TH2 cells in experimental cutaneous leishmaniasis. Exp Parasitol. 1989;68(3):369–72.

    Article  PubMed  CAS  Google Scholar 

  36. Iezzi G, Karjalainen K, Lanzavecchia A. The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity. 1998;8(1):89–95.

    Article  PubMed  CAS  Google Scholar 

  37. Steinman RM, Hemmi H. Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol. 2006;311:17–58.

    PubMed  CAS  Google Scholar 

  38. O’Garra A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity. 1998;8(3):275–83.

    Article  PubMed  Google Scholar 

  39. Bogdan C, Moll H, Solbach W, Rollinghoff M. Tumor necrosis factor-alpha in combination with interferon-gamma, but not with interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes. Eur J Immunol. 1990;20(5):1131–5.

    Article  PubMed  CAS  Google Scholar 

  40. Darrah PA, Patel DT, De Luca PM, Lindsay RW, et al. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med. 2007;13(7):843–50.

    Article  PubMed  CAS  Google Scholar 

  41. Sacks D, Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol. 2002;2(11):845–58.

    Article  PubMed  CAS  Google Scholar 

  42. Scott P, Eaton A, Gause WC, di Zhou X, et al. Early IL-4 production does not predict susceptibility to Leishmania major. Exp Parasitol. 1996;84(2):178–87.

    Article  PubMed  Google Scholar 

  43. Uzonna JE, Spath GF, Beverley SM, Scott P. Vaccination with phosphoglycan-deficient Leishmania major protects highly susceptible mice from virulent challenge without inducing a strong Th1 response. J Immunol. 2004;172(6):3793–7.

    Article  PubMed  CAS  Google Scholar 

  44. Kedzierski L, Curtis JM, Doherty PC, Handman E, et al. Decreased IL-10 and IL-13 production and increased CD44hi T cell recruitment contribute to Leishmania major immunity induced by non-persistent parasites. Eur J Immunol. 2008;38(11):3090–100.

    Article  PubMed  CAS  Google Scholar 

  45. Stober CB, Lange UG, Roberts MT, Alcami A, et al. IL-10 from regulatory T cells determines vaccine efficacy in murine Leishmania major infection. J Immunol. 2005;175(4):2517–24.

    Article  PubMed  CAS  Google Scholar 

  46. Ehrchen JM, Roebrock K, Foell D, Nippe N, et al. Keratinocytes determine Th1 immunity during early experimental leishmaniasis. PLoS Pathog. 2010;6(4):e1000871.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Sunderkotter C, Kunz M, Steinbrink K, Meinardus-Hager G, et al. Resistance of mice to experimental leishmaniasis is associated with more rapid appearance of mature macrophages in vitro and in vivo. J Immunol. 1993;151(9):4891–901.

    PubMed  CAS  Google Scholar 

  48. Himmelrich H, Launois P, Maillard I, Biedermann T, et al. In BALB/c mice, IL-4 production during the initial phase of infection with Leishmania major is necessary and sufficient to instruct Th2 cell development resulting in progressive disease. J Immunol. 2000;164(9):4819–25.

    Article  PubMed  CAS  Google Scholar 

  49. Biedermann T, Zimmermann S, Himmelrich H, Gumy A, et al. IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice. Nat Immunol. 2001;2(11):1054–60.

    Article  PubMed  CAS  Google Scholar 

  50. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005;6(4):353–60.

    Article  PubMed  CAS  Google Scholar 

  51. Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, et al. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature. 2002;420(6915):502–7.

    Article  PubMed  CAS  Google Scholar 

  52. Belkaid Y, Hoffmann KF, Mendez S, Kamhawi S, et al. The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J Exp Med. 2001;194(10):1497–506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Campanelli AP, Roselino AM, Cavassani KA, Pereira MS, et al. CD4+CD25+ T cells in skin lesions of patients with cutaneous leishmaniasis exhibit phenotypic and functional characteristics of natural regulatory T cells. J Infect Dis. 2006;193(9):1313–22.

    Article  PubMed  CAS  Google Scholar 

  54. Bourreau E, Ronet C, Darcissac E, Lise MC, et al. Intralesional regulatory T-cell suppressive function during human acute and chronic cutaneous leishmaniasis due to Leishmania guyanensis. Infect Immun. 2009;77(4):1465–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Hoseini SG, Javanmard SH, Zarkesh SH, Khamesipour A, et al. Regulatory T-cell profile in early and late lesions of cutaneous leishmaniasis due to Leishmania major. J Res Med Sci. 2012;17(6):513–8.

    PubMed  PubMed Central  Google Scholar 

  56. Okwor I, Liu D, Beverley SM, Uzonna JE. Inoculation of killed Leishmania major into immune mice rapidly disrupts immunity to a secondary challenge via IL-10-mediated process. Proc Natl Acad Sci USA. 2009;106(33):13951–6.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Huber M, Timms E, Mak TW, Rollinghoff M, et al. Effective and long-lasting immunity against the parasite Leishmania major in CD8-deficient mice. Infect Immun. 1998;66(8):3968–70.

    PubMed  PubMed Central  CAS  Google Scholar 

  58. Muller I, Kropf P, Etges RJ, Louis JA. Gamma interferon response in secondary Leishmania major infection: role of CD8+ T cells. Infect Immun. 1993;61(9):3730–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  59. Belkaid Y, Von Stebut E, Mendez S, Lira R, et al. CD8+ T cells are required for primary immunity in C57BL/6 mice following low-dose, intradermal challenge with Leishmania major. J Immunol. 2002b;168(8):3992–4000.

    Article  PubMed  CAS  Google Scholar 

  60. Uzonna JE, Joyce KL, Scott P. Low dose Leishmania major promotes a transient T helper cell type 2 response that is down-regulated by interferon gamma-producing CD8+ T cells. J Exp Med. 2004;199(11):1559–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Ruiz JH, Becker I. CD8 cytotoxic T cells in cutaneous leishmaniasis. Parasite Immunol. 2007;29(12):671–8.

    Article  PubMed  CAS  Google Scholar 

  62. Novais FO, Carvalho LP, Graff JW, Beiting DP, et al. Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis. PLoS Pathog. 2013;9(7):e1003504.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Novais FO, Carvalho AM, Clark ML, Carvalho LP, et al. CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1beta production. PLoS Pathog. 2017;13(2):e1006196.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Faria DR, Souza PE, Duraes FV, Carvalho EM, et al. Recruitment of CD8(+) T cells expressing granzyme A is associated with lesion progression in human cutaneous leishmaniasis. Parasite Immunol. 2009;31(8):432–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Santos Cda S, Boaventura V, Ribeiro Cardoso C, Tavares N, et al. CD8(+) granzyme B(+)-mediated tissue injury vs. CD4(+)IFNgamma(+)-mediated parasite killing in human cutaneous leishmaniasis. J Invest Dermatol. 2013;133(6):1533–40.

    Article  PubMed  CAS  Google Scholar 

  66. Cardoso TM, Machado A, Costa DL, Carvalho LP, et al. Protective and pathological functions of CD8+ T cells in Leishmania braziliensis infection. Infect Immun. 2015;83(3):898–906.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Bertholet S, Goldszmid R, Morrot A, Debrabant A, et al. Leishmania antigens are presented to CD8+ T cells by a transporter associated with antigen processing-independent pathway in vitro and in vivo. J Immunol. 2006;177(6):3525–33.

    Article  PubMed  CAS  Google Scholar 

  68. Houde M, Bertholet S, Gagnon E, Brunet S, et al. Phagosomes are competent organelles for antigen cross-presentation. Nature. 2003;425(6956):402–6.

    Article  PubMed  CAS  Google Scholar 

  69. Rodriguez A, Regnault A, Kleijmeer M, Ricciardi-Castagnoli P, et al. Selective transport of internalized antigens to the cytosol for MHC class I presentation in dendritic cells. Nat Cell Biol. 1999;1(6):362–8.

    Article  PubMed  CAS  Google Scholar 

  70. Matheoud D, Moradin N, Bellemare-Pelletier A, Shio MT, et al. Leishmania evades host immunity by inhibiting antigen cross-presentation through direct cleavage of the SNARE VAMP8. Cell Host Microbe. 2013;14(1):15–25.

    Article  PubMed  CAS  Google Scholar 

  71. Ashok D, Schuster S, Ronet C, Rosa M, et al. Cross-presenting dendritic cells are required for control of Leishmania major infection. Eur J Immunol. 2014;44(5):1422–32.

    Article  PubMed  CAS  Google Scholar 

  72. Sacks DL, Scott PA, Asofsky R, Sher FA. Cutaneous leishmaniasis in anti-IgM-treated mice: enhanced resistance due to functional depletion of a B cell-dependent T cell involved in the suppressor pathway. J Immunol. 1984;132(4):2072–7.

    PubMed  CAS  Google Scholar 

  73. Hoerauf A, Solbach W, Rollinghoff M, Gessner A. Effect of IL-7 treatment on Leishmania major-infected BALB.Xid mice: enhanced lymphopoiesis with sustained lack of B1 cells and clinical aggravation of disease. Int Immunol. 1995;7(11):1879–84.

    PubMed  CAS  Google Scholar 

  74. Smelt SC, Cotterell SE, Engwerda CR, Kaye PM. B cell-deficient mice are highly resistant to Leishmania donovani infection, but develop neutrophil-mediated tissue pathology. J Immunol. 2000;164(7):3681–8.

    Article  PubMed  CAS  Google Scholar 

  75. Ronet C, Voigt H, Himmelrich H, Doucey MA, et al. Leishmania major-specific B cells are necessary for Th2 cell development and susceptibility to L. major LV39 in BALB/c mice. J Immunol. 2008;180(7):4825–35.

    Article  PubMed  CAS  Google Scholar 

  76. Ronet C, Hauyon-La Torre Y, Revaz-Breton M, Mastelic B, et al. Regulatory B cells shape the development of Th2 immune responses in BALB/c mice infected with Leishmania major through IL-10 production. J Immunol. 2010;184(2):886–94.

    Article  PubMed  CAS  Google Scholar 

  77. Rodriguez-Pinto D, Saravia NG, McMahon-Pratt D. CD4 T cell activation by B cells in human Leishmania (Viannia) infection. BMC Infect Dis. 2014;14:108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Gollob KJ, Antonelli LR, Faria DR, Keesen TS, et al. Immunoregulatory mechanisms and CD4-CD8- (double negative) T cell subpopulations in human cutaneous leishmaniasis: a balancing act between protection and pathology. Int Immunopharmacol. 2008;8(10):1338–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Liese J, Schleicher U, Bogdan C. The innate immune response against Leishmania parasites. Immunobiology. 2008;213(3-4):377–87.

    Article  PubMed  CAS  Google Scholar 

  80. Rodriguez NE, Wilson ME. Eosinophils and mast cells in leishmaniasis. Immunol Res. 2014;59(1–3):129–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Kopf M, Brombacher F, Kohler G, Kienzle G, et al. IL-4-deficient Balb/c mice resist infection with Leishmania major. J Exp Med. 1996;184(3):1127–36.

    Article  PubMed  CAS  Google Scholar 

  82. Radwanska M, Cutler AJ, Hoving JC, Magez S, et al. Deletion of IL-4Ralpha on CD4 T cells renders BALB/c mice resistant to Leishmania major infection. PLoS Pathog. 2007;3(5):e68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Noben-Trauth N, Kropf P, Muller I. Susceptibility to Leishmania major infection in interleukin-4-deficient mice. Science. 1996;271(5251):987–90.

    Article  PubMed  CAS  Google Scholar 

  84. Alexander J, Brombacher F, McGachy HA, McKenzie AN, et al. An essential role for IL-13 in maintaining a non-healing response following Leishmania mexicana infection. Eur J Immunol. 2002;32(10):2923–33.

    Article  PubMed  CAS  Google Scholar 

  85. Lazarski CA, Ford J, Katzman SD, Rosenberg AF, et al. IL-4 attenuates Th1-associated chemokine expression and Th1 trafficking to inflamed tissues and limits pathogen clearance. PLoS One. 2013;8(8):e71949.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Hurdayal R, Nieuwenhuizen NE, Revaz-Breton M, Smith L, et al. Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection. PLoS Pathog. 2013;9(10):e1003699.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Brombacher F. The role of interleukin-13 in infectious diseases and allergy. BioEssays. 2000;22(7):646–56.

    Article  PubMed  CAS  Google Scholar 

  88. Matthews DJ, Emson CL, McKenzie GJ, Jolin HE, et al. IL-13 is a susceptibility factor for Leishmania major infection. J Immunol. 2000;164(3):1458–62.

    Article  PubMed  CAS  Google Scholar 

  89. Bourreau E, Prevot G, Pradinaud R, Launois P. Interleukin (IL)-13 is the predominant Th2 cytokine in localized cutaneous leishmaniasis lesions and renders specific CD4+ T cells unresponsive to IL-12. J Infect Dis. 2001;183(6):953–9.

    Article  PubMed  CAS  Google Scholar 

  90. Murphy ML, Wille U, Villegas EN, Hunter CA, et al. IL-10 mediates susceptibility to Leishmania donovani infection. Eur J Immunol. 2001;31(10):2848–56.

    Article  PubMed  CAS  Google Scholar 

  91. O’Garra A, Vieira P. T(H)1 cells control themselves by producing interleukin-10. Nat Rev Immunol. 2007;7(6):425–8.

    Article  PubMed  CAS  Google Scholar 

  92. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.

    Article  PubMed  CAS  Google Scholar 

  93. Costa DL, Cardoso TM, Queiroz A, Milanezi CM, et al. Tr-1-like CD4+CD25-CD127-/lowFOXP3- cells are the main source of interleukin 10 in patients with cutaneous leishmaniasis due to Leishmania braziliensis. J Infect Dis. 2015;211(5):708–18.

    Article  PubMed  CAS  Google Scholar 

  94. Silvestre R, Cordeiro-Da-Silva A, Santarem N, Vergnes B, et al. SIR2-deficient Leishmania infantum induces a defined IFN-gamma/IL-10 pattern that correlates with protection. J Immunol. 2007;179(5):3161–70.

    Article  PubMed  CAS  Google Scholar 

  95. Kane MM, Mosser DM. The role of IL-10 in promoting disease progression in leishmaniasis. J Immunol. 2001;166(2):1141–7.

    Article  PubMed  CAS  Google Scholar 

  96. Groux H, Cottrez F, Rouleau M, Mauze S, et al. A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells. J Immunol. 1999;162(3):1723–9.

    PubMed  CAS  Google Scholar 

  97. Padigel UM, Alexander J, Farrell JP. The role of interleukin-10 in susceptibility of BALB/c mice to infection with Leishmania mexicana and Leishmania amazonensis. J Immunol. 2003;171(7):3705–10.

    Article  PubMed  CAS  Google Scholar 

  98. Darrah PA, Hegde ST, Patel DT, Lindsay RW, et al. IL-10 production differentially influences the magnitude, quality, and protective capacity of Th1 responses depending on the vaccine platform. J Exp Med. 2010;207(7):1421–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Anderson CF, Oukka M, Kuchroo VJ, Sacks D. CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J Exp Med. 2007;204(2):285–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Schwarz T, Remer KA, Nahrendorf W, Masic A, et al. T cell-derived IL-10 determines leishmaniasis disease outcome and is suppressed by a dendritic cell based vaccine. PLoS Pathog. 2013;9(6):e1003476.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Gimblet C, Loesche MA, Carvalho L, Carvalho EM, et al. IL-22 protects against tissue damage during cutaneous leishmaniasis. PLoS One. 2015;10(8):e0134698.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Hezarjaribi HZ, Ghaffarifar F, Dalimi A, Sharifi Z. Evaluation of protective effect of IL-22 and IL-12 on cutaneous leishmaniasis in BALB/c mice. Asian Pac J Trop Med. 2014;7(12):940–5.

    Article  PubMed  CAS  Google Scholar 

  103. Demoulin JB, Renauld JC. Interleukin 9 and its receptor: an overview of structure and function. Int Rev Immunol. 1998;16(3–4):345–64.

    Article  PubMed  CAS  Google Scholar 

  104. Kopf M, Le Gros G, Bachmann M, Lamers MC, et al. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature. 1993;362(6417):245–8.

    Article  PubMed  CAS  Google Scholar 

  105. Monteyne P, Renauld JC, Van Broeck J, Dunne DW, et al. IL-4-independent regulation of in vivo IL-9 expression. J Immunol. 1997;159(6):2616–23.

    PubMed  CAS  Google Scholar 

  106. Gessner A, Blum H, Rollinghoff M. Differential regulation of IL-9-expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology. 1993;189(5):419–35.

    Article  PubMed  CAS  Google Scholar 

  107. Arendse B, Van Snick J, Brombacher F. IL-9 is a susceptibility factor in Leishmania major infection by promoting detrimental Th2/type 2 responses. J Immunol. 2005;174(4):2205–11.

    Article  PubMed  CAS  Google Scholar 

  108. Li MO, Wan YY, Sanjabi S, Robertson AK, et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146.

    Article  PubMed  CAS  Google Scholar 

  109. Mougneau E, Bihl F, Glaichenhaus N. Cell biology and immunology of Leishmania. Immunol Rev. 2011;240(1):286–96.

    Article  PubMed  CAS  Google Scholar 

  110. Barral-Netto M, Barral A, Brownell CE, Skeiky YA, et al. Transforming growth factor-beta in leishmanial infection: a parasite escape mechanism. Science. 1992;257(5069):545–8.

    Article  PubMed  CAS  Google Scholar 

  111. Li J, Hunter CA, Farrell JP. Anti-TGF-beta treatment promotes rapid healing of Leishmania major infection in mice by enhancing in vivo nitric oxide production. J Immunol. 1999;162(2):974–9.

    PubMed  CAS  Google Scholar 

  112. Heinzel FP, Rerko RM, Hatam F, Locksley RM. IL-2 is necessary for the progression of leishmaniasis in susceptible murine hosts. J Immunol. 1993;150(9):3924–31.

    PubMed  CAS  Google Scholar 

  113. Mattner F, Magram J, Ferrante J, Launois P, et al. Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response. Eur J Immunol. 1996;26(7):1553–9.

    Article  PubMed  CAS  Google Scholar 

  114. Scott P, Artis D, Uzonna J, Zaph C. The development of effector and memory T cells in cutaneous leishmaniasis: the implications for vaccine development. Immunol Rev. 2004;201:318–38.

    Article  PubMed  CAS  Google Scholar 

  115. Pakpour N, Zaph C, Scott P. The central memory CD4+ T cell population generated during Leishmania major infection requires IL-12 to produce IFN-gamma. J Immunol. 2008;180(12):8299–305.

    Article  PubMed  CAS  Google Scholar 

  116. von Stebut E, Udey MC. Requirements for Th1-dependent immunity against infection with Leishmania major. Microbes Infect. 2004;6(12):1102–9.

    Article  CAS  Google Scholar 

  117. Carrera L, Gazzinelli RT, Badolato R, Hieny S, et al. Leishmania promastigotes selectively inhibit interleukin 12 induction in bone marrow-derived macrophages from susceptible and resistant mice. J Exp Med. 1996;183(2):515–26.

    Article  PubMed  CAS  Google Scholar 

  118. Von Stebut E, Ehrchen JM, Belkaid Y, Kostka SL, et al. Interleukin 1 alpha promotes Th1 differentiation and inhibits disease progression in Leishmania major-susceptible BALB/c mice. J Exp Med. 2003;198(2):191–9.

    Article  CAS  Google Scholar 

  119. Wang ZE, Reiner SL, Zheng S, Dalton DK, et al. CD4+ effector cells default to the Th2 pathway in interferon gamma-deficient mice infected with Leishmania major. J Exp Med. 1994;179(4):1367–71.

    Article  PubMed  CAS  Google Scholar 

  120. Scharton TM, Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J Exp Med. 1993;178(2):567–77.

    Article  PubMed  CAS  Google Scholar 

  121. Satoskar AR, Stamm LM, Zhang X, Satoskar AA, et al. Mice lacking NK cells develop an efficient Th1 response and control cutaneous Leishmania major infection. J Immunol. 1999;162(11):6747–54.

    PubMed  CAS  Google Scholar 

  122. Nacy CA, Meierovics AI, Belosevic M, Green SJ. Tumor necrosis factor-alpha: central regulatory cytokine in the induction of macrophage antimicrobial activities. Pathobiology. 1991;59(3):182–4.

    Article  PubMed  CAS  Google Scholar 

  123. Gessner A, Vieth M, Will A, Schroppel K, et al. Interleukin-7 enhances antimicrobial activity against Leishmania major in murine macrophages. Infect Immun. 1993;61(9):4008–12.

    PubMed  PubMed Central  CAS  Google Scholar 

  124. Swihart K, Fruth U, Messmer N, Hug K, et al. Mice from a genetically resistant background lacking the interferon gamma receptor are susceptible to infection with Leishmania major but mount a polarized T helper cell 1-type CD4+ T cell response. J Exp Med. 1995;181(3):961–71.

    Article  PubMed  CAS  Google Scholar 

  125. Sadick MD, Heinzel FP, Holaday BJ, Pu RT, et al. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990;171(1):115–27.

    Article  PubMed  CAS  Google Scholar 

  126. Anderson CF, Mendez S, Sacks DL. Nonhealing infection despite Th1 polarization produced by a strain of Leishmania major in C57BL/6 mice. J Immunol. 2005;174(5):2934–41.

    Article  PubMed  CAS  Google Scholar 

  127. Havell EA. Evidence that tumor necrosis factor has an important role in antibacterial resistance. J Immunol. 1989;143(9):2894–9.

    PubMed  CAS  Google Scholar 

  128. Titus RG, Sherry B, Cerami A. Tumor necrosis factor plays a protective role in experimental murine cutaneous leishmaniasis. J Exp Med. 1989;170(6):2097–104.

    Article  PubMed  CAS  Google Scholar 

  129. Bacellar O, Faria D, Nascimento M, Cardoso TM, et al. Interleukin 17 production among patients with American cutaneous leishmaniasis. J Infect Dis. 2009;200(1):75–8.

    Article  PubMed  CAS  Google Scholar 

  130. Gonzalez-Lombana C, Gimblet C, Bacellar O, Oliveira WW, et al. IL-17 mediates immunopathology in the absence of IL-10 following Leishmania major infection. PLoS Pathog. 2013;9(3):e1003243.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Moafi M, Rezvan H, Sherkat R, Taleban R, et al. Comparison of pro-inflammatory cytokines of non-healing and healing cutaneous leishmaniasis. Scand J Immunol. 2017;85(4):291–9.

    Article  PubMed  CAS  Google Scholar 

  132. Boulay JL, O’Shea JJ, Paul WE. Molecular phylogeny within type I cytokines and their cognate receptors. Immunity. 2003;19(2):159–63.

    Article  PubMed  CAS  Google Scholar 

  133. Chen Q, Ghilardi N, Wang H, Baker T, et al. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature. 2000;407(6806):916–20.

    Article  PubMed  CAS  Google Scholar 

  134. Yoshida H, Hamano S, Senaldi G, Covey T, et al. WSX-1 is required for the initiation of Th1 responses and resistance to L. major infection. Immunity. 2001;15(4):569–78.

    Article  PubMed  CAS  Google Scholar 

  135. Artis D, Johnson LM, Joyce K, Saris C, et al. Cutting edge: early IL-4 production governs the requirement for IL-27-WSX-1 signaling in the development of protective Th1 cytokine responses following Leishmania major infection. J Immunol. 2004;172(8):4672–5.

    Article  PubMed  CAS  Google Scholar 

  136. Oppmann B, Lesley R, Blom B, Timans JC, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13(5):715–25.

    Article  PubMed  CAS  Google Scholar 

  137. Tan ZY, Bealgey KW, Fang Y, Gong YM, et al. Interleukin-23: immunological roles and clinical implications. Int J Biochem Cell Biol. 2009;41(4):733–5.

    Article  PubMed  CAS  Google Scholar 

  138. Langrish CL, McKenzie BS, Wilson NJ, de Waal Malefyt R, et al. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev. 2004;202:96–105.

    Article  PubMed  CAS  Google Scholar 

  139. Tolouei S, Ghaedi K, Khamesipour A, Akbari M, et al. IL-23 and IL-27 levels in macrophages collected from peripheral blood of patients with healing vs non-healing form of cutaneous leishmaniasis. Iran J Parasitol. 2012;7(1):18–25.

    PubMed  PubMed Central  CAS  Google Scholar 

  140. Diefenbach A, Schindler H, Donhauser N, Lorenz E, et al. Type 1 interferon (IFNalpha/beta) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite. Immunity. 1998;8(1):77–87.

    Article  PubMed  CAS  Google Scholar 

  141. Mattner J, Wandersee-Steinhauser A, Pahl A, Rollinghoff M, et al. Protection against progressive leishmaniasis by IFN-beta. J Immunol. 2004;172(12):7574–82.

    Article  PubMed  CAS  Google Scholar 

  142. Jaramillo M, Gomez MA, Larsson O, Shio MT, et al. Leishmania repression of host translation through mTOR cleavage is required for parasite survival and infection. Cell Host Microbe. 2011;9(4):331–41.

    Article  PubMed  CAS  Google Scholar 

  143. Fernandez-Figueroa EA, Rangel-Escareno C, Espinosa-Mateos V, Carrillo-Sanchez K, et al. Disease severity in patients infected with Leishmania mexicana relates to IL-1beta. PLoS Negl Trop Dis. 2012;6(5):e1533.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Lima-Junior DS, Costa DL, Carregaro V, Cunha LD, et al. Inflammasome-derived IL-1beta production induces nitric oxide-mediated resistance to Leishmania. Nat Med. 2013;19(7):909–15.

    Article  PubMed  CAS  Google Scholar 

  145. Gurung P, Karki R, Vogel P, Watanabe M, et al. An NLRP3 inflammasome-triggered Th2-biased adaptive immune response promotes leishmaniasis. J Clin Invest. 2015;125(3):1329–38.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Charmoy M, Hurrell BP, Romano A, Lee SH, et al. The Nlrp3 inflammasome, IL-1beta, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice. Eur J Immunol. 2016;46(4):897–911.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Gannavaram S, Bhattacharya P, Ismail N, Kaul A, et al. Modulation of innate immune mechanisms to enhance Leishmania vaccine-induced immunity: role of coinhibitory molecules. Front Immunol. 2016;7:187.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Oghumu S, Lezama-Davila CM, Isaac-Marquez AP, Satoskar AR. Role of chemokines in regulation of immunity against leishmaniasis. Exp Parasitol. 2010;126(3):389–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Ajdary S, Alimohammadian MH, Eslami MB, Kemp K, et al. Comparison of the immune profile of nonhealing cutaneous leishmaniasis patients with those with active lesions and those who have recovered from infection. Infect Immun. 2000;68(4):1760–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Khalil EA, Ayed NB, Musa AM, Ibrahim ME, et al. Dichotomy of protective cellular immune responses to human visceral leishmaniasis. Clin Exp Immunol. 2005;140(2):349–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Leclercq V, Lebastard M, Belkaid Y, Louis J, et al. The outcome of the parasitic process initiated by Leishmania infantum in laboratory mice: a tissue-dependent pattern controlled by the Lsh and MHC loci. J Immunol. 1996;157(10):4537–45.

    PubMed  CAS  Google Scholar 

  152. Ali A. Leishmaniases and HIV/AIDS co-infections: review of common features and management experiences. Ethiop Med J. 2002;40(Suppl 1):37–49.

    PubMed  Google Scholar 

  153. Vidal S, Tremblay ML, Govoni G, Gauthier S, et al. The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J Exp Med. 1995;182(3):655–66.

    Article  PubMed  CAS  Google Scholar 

  154. Blackwell JM, Goswami T, Evans CA, Sibthorpe D, et al. SLC11A1 (formerly NRAMP1) and disease resistance. Cell Microbiol. 2001;3(12):773–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Stober CB, Brode S, White JK, Popoff JF, et al. Slc11a1, formerly Nramp1, is expressed in dendritic cells and influences major histocompatibility complex class II expression and antigen-presenting cell function. Infect Immun. 2007;75(10):5059–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Blackwell JM, Barton CH, White JK, Searle S, et al. Genomic organization and sequence of the human NRAMP gene: identification and mapping of a promoter region polymorphism. Mol Med. 1995;1(2):194–205.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Goswami T, Bhattacharjee A, Babal P, Searle S, et al. Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter. Biochem J. 2001;354(Pt 3):511–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Singh OP, Gidwani K, Kumar R, Nylen S, et al. Reassessment of immune correlates in human visceral leishmaniasis as defined by cytokine release in whole blood. Clin Vaccine Immunol. 2012;19(6):961–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Ahmed S, Colmenares M, Soong L, Goldsmith-Pestana K, et al. Intradermal infection model for pathogenesis and vaccine studies of murine visceral leishmaniasis. Infect Immun. 2003;71(1):401–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Miralles GD, Stoeckle MY, McDermott DF, Finkelman FD, et al. Th1 and Th2 cell-associated cytokines in experimental visceral leishmaniasis. Infect Immun. 1994;62(3):1058–63.

    PubMed  PubMed Central  CAS  Google Scholar 

  161. Squires KE, Schreiber RD, McElrath MJ, Rubin BY, et al. Experimental visceral leishmaniasis: role of endogenous IFN-gamma in host defense and tissue granulomatous response. J Immunol. 1989;143(12):4244–9.

    PubMed  CAS  Google Scholar 

  162. Kurkjian KM, Mahmutovic AJ, Kellar KL, Haque R, et al. Multiplex analysis of circulating cytokines in the sera of patients with different clinical forms of visceral leishmaniasis. Cytometry A. 2006;69(5):353–8.

    Article  PubMed  CAS  Google Scholar 

  163. Sundar S, Reed SG, Sharma S, Mehrotra A, et al. Circulating T helper 1 (Th1) cell- and Th2 cell-associated cytokines in Indian patients with visceral leishmaniasis. Am J Trop Med Hyg. 1997;56(5):522–5.

    Article  PubMed  CAS  Google Scholar 

  164. Singh OP, Sundar S. Immunotherapy and targeted therapies in treatment of visceral leishmaniasis: current status and future prospects. Front Immunol. 2014;5:296.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Engwerda CR, Kaye PM. Organ-specific immune responses associated with infectious disease. Immunol Today. 2000;21(2):73–8.

    Article  PubMed  CAS  Google Scholar 

  166. Bohme MW, Evans DA, Miles MA, Holborow EJ. Occurrence of autoantibodies to intermediate filament proteins in human visceral leishmaniasis and their induction by experimental polyclonal B-cell activation. Immunology. 1986;59(4):583–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  167. Galvao-Castro B, Sa Ferreira JA, Marzochi KF, Marzochi MC, et al. Polyclonal B cell activation, circulating immune complexes and autoimmunity in human American visceral leishmaniasis. Clin Exp Immunol. 1984;56(1):58–66.

    PubMed  PubMed Central  CAS  Google Scholar 

  168. Stern JJ, Oca MJ, Rubin BY, Anderson SL, et al. Role of L3T4+ and LyT-2+ cells in experimental visceral leishmaniasis. J Immunol. 1988;140(11):3971–7.

    PubMed  CAS  Google Scholar 

  169. Kaye PM, Bancroft GJ. Leishmania donovani infection in scid mice: lack of tissue response and in vivo macrophage activation correlates with failure to trigger natural killer cell-derived gamma interferon production in vitro. Infect Immun. 1992;60(10):4335–42.

    PubMed  PubMed Central  CAS  Google Scholar 

  170. Alexander CE, Kaye PM, Engwerda CR. CD95 is required for the early control of parasite burden in the liver of Leishmania donovani-infected mice. Eur J Immunol. 2001;31(4):1199–210.

    Article  PubMed  CAS  Google Scholar 

  171. Stager S, Smith DF, Kaye PM. Immunization with a recombinant stage-regulated surface protein from Leishmania donovani induces protection against visceral leishmaniasis. J Immunol. 2000;165(12):7064–71.

    Article  PubMed  CAS  Google Scholar 

  172. Mary C, Auriault V, Faugere B, Dessein AJ. Control of Leishmania infantum infection is associated with CD8(+) and gamma interferon- and interleukin-5-producing CD4(+) antigen-specific T cells. Infect Immun. 1999;67(11):5559–66.

    PubMed  PubMed Central  CAS  Google Scholar 

  173. Joshi T, Rodriguez S, Perovic V, Cockburn IA, et al. B7-H1 blockade increases survival of dysfunctional CD8(+) T cells and confers protection against Leishmania donovani infections. PLoS Pathog. 2009;5(5):e1000431.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Polley R, Stager S, Prickett S, Maroof A, et al. Adoptive immunotherapy against experimental visceral leishmaniasis with CD8+ T cells requires the presence of cognate antigen. Infect Immun. 2006;74(1):773–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Maroof A, Brown N, Smith B, Hodgkinson MR, et al. Therapeutic vaccination with recombinant adenovirus reduces splenic parasite burden in experimental visceral leishmaniasis. J Infect Dis. 2012;205(5):853–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Gautam S, Kumar R, Singh N, Singh AK, et al. CD8 T cell exhaustion in human visceral leishmaniasis. J Infect Dis. 2014;209(2):290–9.

    Article  PubMed  CAS  Google Scholar 

  177. Murphy ML, Cotterell SE, Gorak PM, Engwerda CR, et al. Blockade of CTLA-4 enhances host resistance to the intracellular pathogen, Leishmania donovani. J Immunol. 1998;161(8):4153–60.

    PubMed  CAS  Google Scholar 

  178. Murray HW, Nathan CF. Macrophage microbicidal mechanisms in vivo: reactive nitrogen versus oxygen intermediates in the killing of intracellular visceral Leishmania donovani. J Exp Med. 1999;189(4):741–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Murray HW, Cartelli DM. Killing of intracellular Leishmania donovani by human mononuclear phagocytes. Evidence for oxygen-dependent and -independent leishmanicidal activity. J Clin Invest. 1983;72(1):32–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. McElrath MJ, Murray HW, Cohn ZA. The dynamics of granuloma formation in experimental visceral leishmaniasis. J Exp Med. 1988;167(6):1927–37.

    Article  PubMed  CAS  Google Scholar 

  181. Moore JW, Moyo D, Beattie L, Andrews PS, et al. Functional complexity of the Leishmania granuloma and the potential of in silico modeling. Front Immunol. 2013;4:35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Lachaud L, Bourgeois N, Plourde M, Leprohon P, et al. Parasite susceptibility to amphotericin B in failures of treatment for visceral leishmaniasis in patients coinfected with HIV type 1 and Leishmania infantum. Clin Infect Dis. 2009;48(2):e16–22.

    Article  PubMed  CAS  Google Scholar 

  183. Antinori S, Cascio A, Parravicini C, Bianchi R, et al. Leishmaniasis among organ transplant recipients. Lancet Infect Dis. 2008;8(3):191–9.

    Article  PubMed  Google Scholar 

  184. Beattie L, Peltan A, Maroof A, Kirby A, et al. Dynamic imaging of experimental Leishmania donovani-induced hepatic granulomas detects Kupffer cell-restricted antigen presentation to antigen-specific CD8 T cells. PLoS Pathog. 2010;6(3):e1000805.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Murray HW. Tissue granuloma structure-function in experimental visceral leishmaniasis. Int J Exp Pathol. 2001;82(5):249–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Beattie L, d’El-Rei Hermida M, Moore JW, Maroof A, et al. A transcriptomic network identified in uninfected macrophages responding to inflammation controls intracellular pathogen survival. Cell Host Microbe. 2013;14(3):357–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Cervia JS, Rosen H, Murray HW. Effector role of blood monocytes in experimental visceral leishmaniasis. Infect Immun. 1993;61(4):1330–3.

    PubMed  PubMed Central  CAS  Google Scholar 

  188. Murray HW, Stern JJ, Welte K, Rubin BY, et al. Experimental visceral leishmaniasis: production of interleukin 2 and interferon-gamma, tissue immune reaction, and response to treatment with interleukin 2 and interferon-gamma. J Immunol. 1987;138(7):2290–7.

    PubMed  CAS  Google Scholar 

  189. Moore JW, Beattie L, Dalton JE, Owens BM, et al. B cell: T cell interactions occur within hepatic granulomas during experimental visceral leishmaniasis. PLoS One. 2012;7(3):e34143.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Cotterell SE, Engwerda CR, Kaye PM. Leishmania donovani infection initiates T cell-independent chemokine responses, which are subsequently amplified in a T cell-dependent manner. Eur J Immunol. 1999;29(1):203–14.

    Article  PubMed  CAS  Google Scholar 

  191. Dey R, Majumder N, Bhattacharyya Majumdar S, Bhattacharjee S, et al. Induction of host protective Th1 immune response by chemokines in Leishmania donovani-infected BALB/c mice. Scand J Immunol. 2007;66(6):671–83.

    Article  PubMed  CAS  Google Scholar 

  192. Sato N, Kuziel WA, Melby PC, Reddick RL, et al. Defects in the generation of IFN-gamma are overcome to control infection with Leishmania donovani in CC chemokine receptor (CCR) 5-, macrophage inflammatory protein-1 alpha-, or CCR2-deficient mice. J Immunol. 1999;163(10):5519–25.

    PubMed  CAS  Google Scholar 

  193. Stanley AC, Engwerda CR. Balancing immunity and pathology in visceral leishmaniasis. Immunol Cell Biol. 2007;85(2):138–47.

    Article  PubMed  CAS  Google Scholar 

  194. Engwerda CR, Smelt SC, Kaye PM. An in vivo analysis of cytokine production during Leishmania donovani infection in scid mice. Exp Parasitol. 1996;84(2):195–202.

    Article  PubMed  CAS  Google Scholar 

  195. Murray HW, Squires KE, Miralles CD, Stoeckle MY, et al. Acquired resistance and granuloma formation in experimental visceral leishmaniasis. Differential T cell and lymphokine roles in initial versus established immunity. J Immunol. 1992;148(6):1858–63.

    PubMed  CAS  Google Scholar 

  196. Tsagozis P, Karagouni E, Dotsika E. CD8(+) T cells with parasite-specific cytotoxic activity and a Tc1 profile of cytokine and chemokine secretion develop in experimental visceral leishmaniasis. Parasite Immunol. 2003;25(11–12):569–79.

    Article  PubMed  CAS  Google Scholar 

  197. Ghalib HW, Whittle JA, Kubin M, Hashim FA, et al. IL-12 enhances Th1-type responses in human Leishmania donovani infections. J Immunol. 1995;154(9):4623–9.

    PubMed  CAS  Google Scholar 

  198. Tumang MC, Keogh C, Moldawer LL, Helfgott DC, et al. Role and effect of TNF-alpha in experimental visceral leishmaniasis. J Immunol. 1994;153(2):768–75.

    PubMed  CAS  Google Scholar 

  199. Engwerda CR, Ato M, Stager S, Alexander CE, et al. Distinct roles for lymphotoxin-alpha and tumor necrosis factor in the control of Leishmania donovani infection. Am J Pathol. 2004;165(6):2123–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Murray HW, Cervia JS, Hariprashad J, Taylor AP, et al. Effect of granulocyte-macrophage colony-stimulating factor in experimental visceral leishmaniasis. J Clin Invest. 1995;95(3):1183–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Murray HW, Miralles GD, Stoeckle MY, McDermott DF. Role and effect of IL-2 in experimental visceral leishmaniasis. J Immunol. 1993;151(2):929–38.

    PubMed  CAS  Google Scholar 

  202. Murray HW. Endogenous interleukin-12 regulates acquired resistance in experimental visceral leishmaniasis. J Infect Dis. 1997;175(6):1477–9.

    Article  PubMed  CAS  Google Scholar 

  203. Taylor AP, Murray HW. Intracellular antimicrobial activity in the absence of interferon-gamma: effect of interleukin-12 in experimental visceral leishmaniasis in interferon-gamma gene-disrupted mice. J Exp Med. 1997;185(7):1231–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Murray HW, Hariprashad J, Aguero B, Arakawa T, et al. Antimicrobial response of a T cell-deficient host to cytokine therapy: effect of interferon-gamma in experimental visceral leishmaniasis in nude mice. J Infect Dis. 1995;171(5):1309–16.

    Article  PubMed  CAS  Google Scholar 

  205. Murray HW. Effect of continuous administration of interferon-gamma in experimental visceral leishmaniasis. J Infect Dis. 1990;161(5):992–4.

    Article  PubMed  CAS  Google Scholar 

  206. Badaro R, Johnson WD Jr. The role of interferon-gamma in the treatment of visceral and diffuse cutaneous leishmaniasis. J Infect Dis. 1993;167(Suppl 1):S13–7.

    Article  PubMed  Google Scholar 

  207. Murray HW, Jungbluth A, Ritter E, Montelibano C, et al. Visceral leishmaniasis in mice devoid of tumor necrosis factor and response to treatment. Infect Immun. 2000;68(11):6289–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Stager S, Alexander J, Carter KC, Brombacher F, et al. Both interleukin-4 (IL-4) and IL-4 receptor alpha signaling contribute to the development of hepatic granulomas with optimal antileishmanial activity. Infect Immun. 2003;71(8):4804–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Wilson ME, Young BM, Davidson BL, Mente KA, et al. The importance of TGF-beta in murine visceral leishmaniasis. J Immunol. 1998;161(11):6148–55.

    PubMed  CAS  Google Scholar 

  210. Murray HW. Accelerated control of visceral Leishmania donovani infection in interleukin-6-deficient mice. Infect Immun. 2008;76(9):4088–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  211. Rosas LE, Satoskar AA, Roth KM, Keiser TL, et al. Interleukin-27R (WSX-1/T-cell cytokine receptor) gene-deficient mice display enhanced resistance to Leishmania donovani infection but develop severe liver immunopathology. Am J Pathol. 2006;168(1):158–69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Rostan O, Gangneux JP, Piquet-Pellorce C, Manuel C, et al. The IL-33/ST2 axis is associated with human visceral leishmaniasis and suppresses Th1 responses in the livers of BALB/c mice infected with Leishmania donovani. MBio. 2013;4(5):e00383–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Nascimento MS, Carregaro V, Lima-Junior DS, Costa DL, et al. Interleukin 17A acts synergistically with interferon gamma to promote protection against Leishmania infantum infection. J Infect Dis. 2015;211(6):1015–26.

    Article  PubMed  CAS  Google Scholar 

  214. Ghalib HW, Piuvezam MR, Skeiky YA, Siddig M, et al. Interleukin 10 production correlates with pathology in human Leishmania donovani infections. J Clin Invest. 1993;92(1):324–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Murray HW, Moreira AL, Lu CM, DeVecchio JL, et al. Determinants of response to interleukin-10 receptor blockade immunotherapy in experimental visceral leishmaniasis. J Infect Dis. 2003;188(3):458–64.

    Article  PubMed  CAS  Google Scholar 

  216. Bogdan C, Vodovotz Y, Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991;174(6):1549–55.

    Article  PubMed  CAS  Google Scholar 

  217. Bhattacharyya S, Ghosh S, Jhonson PL, Bhattacharya SK, et al. Immunomodulatory role of interleukin-10 in visceral leishmaniasis: defective activation of protein kinase C-mediated signal transduction events. Infect Immun. 2001;69(3):1499–507.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Stager S, Maroof A, Zubairi S, Sanos SL, et al. Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10+ CD4+ T cells. Eur J Immunol. 2006;36(7):1764–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Owens BM, Beattie L, Moore JW, Brown N, et al. IL-10-producing Th1 cells and disease progression are regulated by distinct CD11c(+) cell populations during visceral leishmaniasis. PLoS Pathog. 2012;8(7):e1002827.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Svensson M, Zubairi S, Maroof A, Kazi F, et al. Invariant NKT cells are essential for the regulation of hepatic CXCL10 gene expression during Leishmania donovani infection. Infect Immun. 2005;73(11):7541–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. Kirkpatrick CE, Farrell JP, Warner JF, Denner G. Participation of natural killer cells in the recovery of mice from visceral leishmaniasis. Cell Immunol. 1985;92(1):163–71.

    Article  PubMed  CAS  Google Scholar 

  222. Amprey JL, Im JS, Turco SJ, Murray HW, et al. A subset of liver NK T cells is activated during Leishmania donovani infection by CD1d-bound lipophosphoglycan. J Exp Med. 2004;200(7):895–904.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Beattie L, Svensson M, Bune A, Brown N, et al. Leishmania donovani-induced expression of signal regulatory protein alpha on Kupffer cells enhances hepatic invariant NKT-cell activation. Eur J Immunol. 2010;40(1):117–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Karmakar S, Bhaumik SK, Paul J, De T. TLR4 and NKT cell synergy in immunotherapy against visceral leishmaniasis. PLoS Pathog. 2012;8(4):e1002646.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  225. Stanley AC, Zhou Y, Amante FH, Randall LM, et al. Activation of invariant NKT cells exacerbates experimental visceral leishmaniasis. PLoS Pathog. 2008;4(2):e1000028.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  226. Zijlstra EE, el-Hassan AM. Leishmaniasis in Sudan. Visceral leishmaniasis. Trans R Soc Trop Med Hyg. 2001;95(Suppl 1):S27–58.

    Article  PubMed  Google Scholar 

  227. Polley R, Zubairi S, Kaye PM. The fate of heterologous CD4+ T cells during Leishmania donovani infection. Eur J Immunol. 2005;35(2):498–504.

    Article  PubMed  Google Scholar 

  228. Phillips R, Svensson M, Aziz N, Maroof A, et al. Innate killing of Leishmania donovani by macrophages of the splenic marginal zone requires IRF-7. PLoS Pathog. 2010;6(3):e1000813.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  229. Ato M, Maroof A, Zubairi S, Nakano H, et al. Loss of dendritic cell migration and impaired resistance to Leishmania donovani infection in mice deficient in CCL19 and CCL21. J Immunol. 2006;176(9):5486–93.

    Article  PubMed  CAS  Google Scholar 

  230. Engwerda CR, Murphy ML, Cotterell SE, Smelt SC, et al. Neutralization of IL-12 demonstrates the existence of discrete organ-specific phases in the control of Leishmania donovani. Eur J Immunol. 1998;28(2):669–80.

    Article  PubMed  CAS  Google Scholar 

  231. Stanley AC, Dalton JE, Rossotti SH, MacDonald KP, et al. VCAM-1 and VLA-4 modulate dendritic cell IL-12p40 production in experimental visceral leishmaniasis. PLoS Pathog. 2008;4(9):e1000158.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  232. Nylen S, Maurya R, Eidsmo L, Manandhar KD, et al. Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis. J Exp Med. 2007;204(4):805–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Gupta G, Bhattacharjee S, Bhattacharyya S, Bhattacharya P, et al. CXC chemokine-mediated protection against visceral leishmaniasis: involvement of the proinflammatory response. J Infect Dis. 2009;200(8):1300–10.

    Article  PubMed  CAS  Google Scholar 

  234. Resende M, Moreira D, Augusto J, Cunha J, et al. Leishmania-infected MHC class II high dendritic cells polarize CD4+ T cells toward a nonprotective T-bet+ IFN-gamma+ IL-10+ phenotype. J Immunol. 2013;191(1):262–73.

    Article  PubMed  CAS  Google Scholar 

  235. McFarlane E, Perez C, Charmoy M, Allenbach C, et al. Neutrophils contribute to development of a protective immune response during onset of infection with Leishmania donovani. Infect Immun. 2008;76(2):532–41.

    Article  PubMed  CAS  Google Scholar 

  236. Rousseau D, Demartino S, Ferrua B, Michiels JF, et al. In vivo involvement of polymorphonuclear neutrophils in Leishmania infantum infection. BMC Microbiol. 2001;1:17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Wilson ME, Recker TJ, Rodriguez NE, Young BM, et al. The TGF-beta response to Leishmania chagasi in the absence of IL-12. Eur J Immunol. 2002;32(12):3556–65.

    Article  PubMed  CAS  Google Scholar 

  238. Maroof A, Beattie L, Zubairi S, Svensson M, et al. Posttranscriptional regulation of II10 gene expression allows natural killer cells to express immunoregulatory function. Immunity. 2008;29(2):295–305.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  239. Bankoti R, Gupta K, Levchenko A, Stager S. Marginal zone B cells regulate antigen-specific T cell responses during infection. J Immunol. 2012;188(8):3961–71.

    Article  PubMed  CAS  Google Scholar 

  240. Engwerda CR, Ato M, Cotterell SE, Mynott TL, et al. A role for tumor necrosis factor-alpha in remodeling the splenic marginal zone during Leishmania donovani infection. Am J Pathol. 2002;161(2):429–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  241. Ato M, Stager S, Engwerda CR, Kaye PM. Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis. Nat Immunol. 2002;3(12):1185–91.

    Article  PubMed  CAS  Google Scholar 

  242. Karplus TM, Jeronimo SM, Chang H, Helms BK, et al. Association between the tumor necrosis factor locus and the clinical outcome of Leishmania chagasi infection. Infect Immun. 2002;70(12):6919–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  243. Ghose AC, Haldar JP, Pal SC, Mishra BP, et al. Serological investigations on Indian kala-azar. Clin Exp Immunol. 1980;40(2):318–26.

    PubMed  PubMed Central  CAS  Google Scholar 

  244. Anam K, Afrin F, Banerjee D, Pramanik N, et al. Differential decline in Leishmania membrane antigen-specific immunoglobulin G (IgG), IgM, IgE, and IgG subclass antibodies in Indian kala-azar patients after chemotherapy. Infect Immun. 1999;67(12):6663–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  245. Pontes De Carvalho LC, Badaro R, Carvalho EM, Lannes-Vieira J, et al. Nature and incidence of erythrocyte-bound IgG and some aspects of the physiopathogenesis of anaemia in American visceral leishmaniasis. Clin Exp Immunol. 1986;64(3):495–502.

    PubMed  PubMed Central  CAS  Google Scholar 

  246. Deak E, Jayakumar A, Cho KW, Goldsmith-Pestana K, et al. Murine visceral leishmaniasis: IgM and polyclonal B-cell activation lead to disease exacerbation. Eur J Immunol. 2010;40(5):1355–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  247. Smelt SC, Engwerda CR, McCrossen M, Kaye PM. Destruction of follicular dendritic cells during chronic visceral leishmaniasis. J Immunol. 1997;158(8):3813–21.

    PubMed  CAS  Google Scholar 

  248. Dalton JE, Maroof A, Owens BM, Narang P, et al. Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice. J Clin Invest. 2010;120(4):1204–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lukasz Kedzierski .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kedzierski, L., Evans, K.J. (2018). The Role of the Immune System in Resistance to Infection. In: Ponte-Sucre, A., Padrón-Nieves, M. (eds) Drug Resistance in Leishmania Parasites. Springer, Cham. https://doi.org/10.1007/978-3-319-74186-4_5

Download citation

Publish with us

Policies and ethics