Skip to main content
×
Home

Subversion of host cell signalling by the protozoan parasite Leishmania

  • D. J. GREGORY (a1) and M. OLIVIER (a1) (a2)
Abstract

The protozoa Leishmania spp. are obligate intracellular parasites that inhabit the macrophages of their host. Since macrophages are specialized for the identification and destruction of invading pathogens, both directly and by triggering an innate immune response, Leishmania have evolved a number of mechanisms for suppressing some critical macrophage activities. In this review, we discuss how various species of Leishmania distort the host macrophage's own signalling pathways to repress the expression of various cytokines and microbicidal molecules (nitric oxide and reactive oxygen species), and antigen presentation. In particular, we describe how MAP Kinase and JAK/STAT cascades are repressed, and intracellular Ca2+ and the activities of protein tyrosine phosphatases, in particular SHP-1, are elevated.

Copyright
Corresponding author
McGill University, Department of Microbiology and Immunology, Duff Medical Building, Room 610, 3775 University Street, Montréal, Québec, H3A 2B4, Canada. Tel: 514-398-5592/1302. Fax: 514-398-7052. E-mail: martin.olivier@mcgill.ca
References
Hide All

REFERENCES

AWASTHI, A., MATHUR, R., KHAN, A., JOSHI, B. N., JAIN, N., SAWANT, S., BOPPANA, R., MITRA, D. & SAHA, B. ( 2003). CD40 signaling is impaired in L. major-infected macrophages and is rescued by a p38MAPK activator establishing a host-protective memory T cell response. Journal of Experimental Medicine 197, 10371043.
BELKAID, Y., BUTCHER, B. & SACKS, D. L. ( 1998). Analysis of cytokine production by inflammatory mouse macrophages at the single-cell level: selective impairment of IL-12 induction in Leishmania-infected cells. European Journal of Immunology 28, 13891400.
BHATTACHARYYA, S., GHOSH, S., JHONSON, P. L., BHATTACHARYA, S. K. & MAJUMDAR, S. ( 2001 a). Immunomodulatory role of interleukin-10 in visceral leishmaniasis: defective activation of protein kinase C-mediated signal transduction events. Infection and Immunity 69, 14991507.
BHATTACHARYYA, S., GHOSH, S., SEN, P., ROY, S. & MAJUMDAR, S. ( 2001 b). Selective impairment of protein kinase C isotypes in murine macrophage by Leishmania donovani. Molecular and Cellular Biochemistry 216, 4757.
BLANCHETTE, J., RACETTE, N., FAURE, R., SIMINOVITCH, K. A. & OLIVIER, M. ( 1999). Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-gamma-triggered JAK2 activation. European Journal of Immunology 29, 37373744.
BUCHMULLER-ROUILLER, Y. & MAUEL, J. ( 1981). Studies on the mechanisms of macrophage activation – possible involvement of oxygen metabolites in killing of Leishmania-Enriettii by activated mouse macrophages. Journal of the Reticuloendothelial Society 29, 181192.
BUCHMULLER-ROUILLER, Y. & MAUEL, J. ( 1986). Correlation between enhanced oxidative metabolism and leishmanicidal activity in activated macrophages from healer and nonhealer mouse strains. Journal of Immunology 136, 38843890.
BUCHMULLER-ROUILLER, Y. & MAUEL, J. ( 1987). Impairment of macrophage oxidative-metabolism by Leishmania. Experientia 43, 665665.
CAMPBELL, K. A., OVENDALE, P. J., KENNEDY, M. K., FANSLOW, W. C., REED, S. G. & MALISZEWSKI, C. R. ( 1996). CD40 ligand is required for protective cell-mediated immunity to Leishmania major. Immunity 4, 283289.
CARRERA, L., GAZZINELLI, R. T., BADOLATO, R., HIENY, S., MULLER, W., KUHN, R. & SACKS, D. L. ( 1996). Leishmania promastigotes selectively inhibit interleukin 12 induction in bone marrow-derived macrophages from susceptible and resistant mice. Journal of Experimental Medicine 183, 515526.
COURRET, N., PRINA, E., MOUGNEAU, E., SARAIVA, E. M., SACKS, D. L., GLAICHENHAUS, N. & ANTOINE, J. C. ( 1999). Presentation of the Leishmania antigen LACK by infected macrophages is dependent upon the virulence of the phagocytosed parasites. European Journal of Immunology 29, 762773.
DAS, S., SAHA, A. K., REMALEY, A. T., GLEW, R. H., DOWLING, J. N., KAJIYOSHI, M. & GOTTLIEB, M. ( 1986). Hydrolysis of phosphoproteins and inositol phosphates by cell surface phosphatase of Leishmania donovani. Molecular and Biochemical Parasitology 20, 143153.
DE ALMEIDA, M. C., CARDOSO, S. A. & BARRAL-NETTO, M. ( 2003). Leishmania (Leishmania) chagasi infection alters the expression of cell adhesion and costimulatory molecules on human monocyte and macrophage. International Journal for Parasitology 33, 153162.
DE SOUZA LEAO S., LANG, T., PRINA, E., HELLIO, R. & ANTOINE, J. C. ( 1995). Intracellular Leishmania amazonensis amastigotes internalize and degrade MHC class II molecules of their host cells. Journal of Cell Science 108, 32193231.
DESCOTEAUX, A. & MATLASHEWSKI, G. ( 1989). c-fos and tumor necrosis factor gene expression in Leishmania donovani-infected macrophages. Molecular Cell Biology 9, 52235227.
DESCOTEAUX, A., MATLASHEWSKI, G. & TURCO, S. J. ( 1992). Inhibition of macrophage protein kinase C-mediated protein phosphorylation by Leishmania donovani lipophosphoglycan. Journal of Immunology 149, 30083015.
DESCOTEAUX, A. & TURCO, S. J. ( 1999). Glycoconjugates in Leishmania infectivity. Biochimica et Biophysica Acta 1455, 341352.
DESJEUX, P. ( 2004). Leishmaniasis. Nature Reviews Microbiology 2, 692.
EILAM, Y., EL ON, J. & SPIRA, D. T. ( 1985). Leishmania major: excreted factor, calcium ions, and the survival of amastigotes. Experimental Parasitology 59, 161168.
FORGET, G., SIMINOVITCH, K. A., BROCHU, S., RIVEST, S., RADZIOCH, D. & OLIVIER, M. ( 2001). Role of host phosphotyrosine phosphatase SHP-1 in the development of murine leishmaniasis. European Journal of Immunology 31, 31853196.
FRANKENBURG, S., LEIBOVICI, V., MANSBACH, N., TURCO, S. J. & ROSEN, G. ( 1990). Effect of glycolipids of Leishmania parasites on human monocyte activity. Inhibition by lipophosphoglycan. Journal of Immunology 145, 42844289.
FRUTH, U., SOLIOZ, N. & LOUIS, J. A. ( 1993). Leishmania major interferes with antigen presentation by infected macrophages. Journal of Immunology 150, 18571864.
GHOSH, S., BHATTACHARYYA, S., DAS, S., RAHA, S., MAULIK, N., DAS, D. K., ROY, S. & MAJUMDAR, S. ( 2001). Generation of ceramide in murine macrophages infected with Leishmania donovani alters macrophage signaling events and aids intracellular parasitic survival. Molecular and Cellular Biochemistry 223, 4760.
GHOSH, S., BHATTACHARYYA, S., SIRKAR, M., SA, G. S., DAS, T., MAJUMDAR, D., ROY, S. & MAJUMDAR, S. ( 2002). Leishmania donovani suppresses activated protein 1 and NF-kappaB activation in host macrophages via ceramide generation: involvement of extracellular signal-regulated kinase. Infection and Immunity 70, 68286838.
HATZIGEORGIOU, D. E., GENG, J., ZHU, B., ZHANG, Y., LIU, K., ROM, W. N., FENTON, M. J., TURCO, S. J. & HO, J. L. ( 1996). Lipophosphoglycan from Leishmania suppresses agonist-induced interleukin 1 beta gene expression in human monocytes via a unique promoter sequence. Proceedings of the National Academy of Sciences, USA 93, 1470814713.
HAWN, T. R., OZINSKY, A., UNDERHILL, D. M., BUCKNER, F. S., AKIRA, S. & ADEREM, A. ( 2002). Leishmania major activates IL-1 alpha expression in macrophages through a MyD88-dependent pathway. Microbes and Infection 4, 763771.
HEINZEL, F. P., RERKO, R. M. & HUJER, A. M. ( 1998). Underproduction of interleukin-12 in susceptible mice during progressive leishmaniasis is due to decreased CD40 activity. Cellular Immunology 184, 129142.
HERWALDT, B. L. ( 1999). Leishmaniasis. Lancet 354, 11911199.
HUBER, M., TIMMS, E., MAK, T. W., ROLLINGHOFF, M. & LOHOFF, M. ( 1998). Effective and long-lasting immunity against the parasite Leishmania major in CD8-deficient mice. Infection and Immunity 66, 39683970.
JUNGHAE, M. & RAYNES, J. G. ( 2002). Activation of p38 mitogen-activated protein kinase attenuates Leishmania donovani infection in macrophages. Infection and Immunity 70, 50265035.
KAMANAKA, M., YU, P., YASUI, T., YOSHIDA, K., KAWABE, T., HORII, T., KISHIMOTO, T. & KIKUTANI, H. ( 1996). Protective role of CD40 in Leishmania major infection at two distinct phases of cell-mediated immunity. Immunity 4, 275281.
KANE, M. M. & MOSSER, D. M. ( 2000). Leishmania parasites and their ploys to disrupt macrophage activation. Current Opinion in Hematology 7, 2631.
KAYE, P. M., ROGERS, N. J., CURRY, A. J. & SCOTT, J. C. ( 1994). Deficient expression of co-stimulatory molecules on Leishmania-infected macrophages. European Journal of Immunology 24, 28502854.
KIMA, P. E., RUDDLE, N. H. & MCMAHON-PRATT, D. ( 1997). Presentation via the class I pathway by Leishmania amazonensis-infected macrophages of an endogenous leishmanial antigen to CD8+T cells. Journal of Immunology 159, 18281834.
KIMA, P. E., SOONG, L., CHICHARRO, C., RUDDLE, N. H. & McMAHON-PRATT, D. ( 1996). Leishmania-infected macrophages sequester endogenously synthesized parasite antigens from presentation to CD4+ T cells. European Journal of Immunology 26, 31633169.
KWAN, W. C., MCMASTER, W. R., WONG, N. & REINER, N. E. ( 1992). Inhibition of expression of major histocompatibility complex class II molecules in macrophages infected with Leishmania donovani occurs at the level of gene transcription via a cyclic AMP-independent mechanism. Infection and Immunity 60, 21152120.
LANG, T., DE CHASTELLIER, C., FREHEL, C., HELLIO, R., METEZEAU, P., LEAO, S. S. & ANTOINE, J. C. ( 1994 a). Distribution of MHC class I and of MHC class II molecules in macrophages infected with Leishmania amazonensis. Journal of Cell Science 107, 6982.
LANG, T., HELLIO, R., KAYE, P. M. & ANTOINE, J. C. ( 1994 b). Leishmania donovani-infected macrophages: characterization of the parasitophorous vacuole and potential role of this organelle in antigen presentation. Journal of Cell Science 107, 21372150.
LIEW, F. Y., MILLOTT, S., PARKINSON, C., PALMER, R. M. & MONCADA, S. ( 1990). Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. Journal of Immunology 144, 47944797.
LOCKSLEY, R. M., REINER, S. L., HATAM, F., LITTMAN, D. R. & KILLEEN, N. ( 1993). Helper T cells without CD4: control of leishmaniasis in CD4-deficient mice. Science 261, 14481451.
MANSFIELD, J. M. & OLIVIER, M. ( 2002). Immune Evasion by Parasites. In Immunology of Infectious Diseases ( ed. Kaufmann, S. H. E., Sher, A. & Ahmed, R.), pp. 379392. ASM Press, Washington, DC.
MARTH, T. & KELSALL, B. L. ( 1997). Regulation of interleukin-12 by complement receptor 3 signaling. Journal of Experimental Medicine 185, 19871995.
MARTINY, A., MEYER-FERNANDES, J. R., DE SOUZA, W. & VANNIER-SANTOS, M. A. ( 1999). Altered tyrosine phosphorylation of ERK1 MAP kinase and other macrophage molecules caused by Leishmania amastigotes. Molecular and Biochemical Parasitology 102, 112.
MATTE, C., MARQUIS, J. F., BLANCHETTE, J., GROS, P., FAURE, R., POSNER, B. I. & OLIVIER, M. ( 2000). Peroxovanadium-mediated protection against murine leishmaniasis: role of the modulation of nitric oxide. European Journal of Immunology 30, 25552564.
MATTE, C. & OLIVIER, M. ( 2002). Leishmania-induced cellular recruitment during the early inflammatory response: modulation of proinflammatory mediators. Journal of Infectious Disease 185, 673681.
McNEELY, T. B., ROSEN, G., LONDNER, M. V. & TURCO, S. J. ( 1989). Inhibitory effects on protein kinase C activity by lipophosphoglycan fragments and glycosylphosphatidylinositol antigens of the protozoan parasite Leishmania. Biochemical Journal 259, 601604.
McNEELY, T. B. & TURCO, S. J. ( 1987). Inhibition of protein kinase C activity by the Leishmania donovani lipophosphoglycan. Biochemical and Biophysical Research Communications 148, 653657.
MURRAY, H. W. ( 1982). Cell-mediated immune response in experimental visceral leishmaniasis. II. Oxygen-dependent killing of intracellular Leishmania donovani amastigotes. Journal of Immunology 129, 351357.
MURRAY, H. W. & NATHAN, C. F. ( 1999). Macrophage microbicidal mechanisms in vivo: reactive nitrogen versus oxygen intermediates in the killing of intracellular visceral Leishmania donovani. Journal of Experimental Medicine 189, 741746.
NANDAN, D., LO, R. & REINER, N. E. ( 1999). Activation of phosphotyrosine phosphatase activity attenuates mitogen-activated protein kinase signaling and inhibits c-FOS and nitric oxide synthase expression in macrophages infected with Leishmania donovani. Infection and Immunity 67, 40554063.
NANDAN, D. & REINER, N. E. ( 1995). Attenuation of gamma-interferon-induced tyrosine phosphorylation in mononuclear phagocytes infected with Leishmania donovani – selective-inhibition of signaling through Janus Kinases and Stat1. Infection and Immunity 63, 44954500.
NANDAN, D. & REINER, N. E. ( 2005). Leishmania donovani engages in regulatory interference by targeting macrophage protein tyrosine phosphatase SHP-1. Clinical Immunology 114, 266277.
NANDAN, D., YI, T. L., LOPEZ, M., LAI, C. & REINER, N. E. ( 2002). Leishmania EF-1 alpha activates the Src homology 2 domain containing tyrosine phosphatase SHP-1 leading to macrophage deactivation. Journal of Biological Chemistry 277, 5019050197.
OLIVIER, M. ( 1996). Modulation of host cell intracellular Ca2+. Parasitology Today 12, 145150.
OLIVIER, M., BAIMBRIDGE, K. G. & REINER, N. E. ( 1992). Stimulus-response coupling in monocytes infected with Leishmania – attenuation of calcium transients is related to defective agonist-induced accumulation of inositol phosphates. Journal of Immunology 148, 11881196.
OLIVIER, M., BROWNSEY, R. W. & REINER, N. E. ( 1992). Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation and translocation of protein-kinase-C. Proceedings of the National Academy of Sciences, USA 89, 74817485.
PIEDRAFITA, D., PROUDFOOT, L., NIKOLAEV, A. V., XU, D. M., SANDS, W., FENG, G. J., THOMAS, E., BREWER, J., FERGUSON, M. A. J., ALEXANDER, J. & LIEW, F. Y. ( 1999). Regulation of macrophage IL-12 synthesis by Leishmania phosphoglycans. European Journal of Immunology 29, 235244.
PRINA, E., JOUANNE, C., DE SOUZA, L. S., SZABO, A., GUILLET, J. G. & ANTOINE, J. C. ( 1993). Antigen presentation capacity of murine macrophages infected with Leishmania amazonensis amastigotes. Journal of Immunology 151, 20502061.
PRIVE, C. & DESCOTEAUX, A. ( 2000). Leishmania donovani promastigotes evade the activation of mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase-1/2 during infection of naive macrophages. European Journal of Immunology 30, 22352244.
PROUDFOOT, L., NIKOLAEV, A. V., FENG, G. J., WEI, W. Q., FERGUSON, M. A., BRIMACOMBE, J. S. & LIEW, F. Y. ( 1996). Regulation of the expression of nitric oxide synthase and leishmanicidal activity by glycoconjugates of Leishmania lipophosphoglycan in murine macrophages. Proceedings of the National Academy of Sciences, USA 93, 1098410989.
PROUDFOOT, L., O'DONNELL, C. A. & LIEW, F. Y. ( 1995). Glycoinositolphospholipids of Leishmania major inhibit nitric oxide synthesis and reduce leishmanicidal activity in murine macrophages. European Journal of Immunology 25, 745750.
RACOOSIN, E. L. & BEVERLEY, S. M. ( 1997). Leishmania major: promastigotes induce expression of a subset of chemokine genes in murine macrophages. Experimental Parasitology 85, 283295.
RAY, M., GAM, A. A., BOYKINS, R. A. & KENNEY, R. T. ( 2000). Inhibition of interferon-gamma signaling by Leishmania donovani. Journal of Infectious Diseases 181, 11211128.
REINER, N. E. ( 1987). Parasite accessory cell-interactions in murine leishmaniasis.1. Evasion and stimulus-dependent suppression of the macrophage interleukin-1 response by Leishmania-donovani. Journal of Immunology 138, 19191925.
REINER, N. E., NG, W., MA, T. & McMASTER, W. R. ( 1988). Macrophages infected with Leishmania-donovani have suppressed responses to interferon-gamma for the induction of major histocompatibility complex class-Ii messenger-RNA. Clinical Research 36, A468A468.
REINER, N. E., NG, W. & McMASTER, W. R. ( 1987). Parasite-accessory cell-interactions in murine leishmaniasis 2. Leishmania donovani suppresses macrophage expression of class-I and class-Ii major histocompatibility complex gene-products. Journal of Immunology 138, 19261932.
SAHA, B., DAS, G., VOHRA, H., GANGULY, N. K. & MISHRA, G. C. ( 1995). Macrophage-T cell interaction in experimental visceral leishmaniasis: failure to express costimulatory molecules on Leishmania-infected macrophages and its implication in the suppression of cell-mediated immunity. European Journal of Immunology 25, 24922498.
SOONG, L., XU, J. C., GREWAL, I. S., KIMA, P., SUN, J., LONGLEY, B. J., RUDDLE, N. H., McMAHON-PRATT, D. & FLAVELL, R. A. ( 1996). Disruption of CD40-CD40 ligand interactions results in an enhanced susceptibility to Leishmania amazonensis infection. Immunity 4, 263273.
SORENSEN, A. L., HEY, A. S. & KHARAZMI, A. ( 1994). Leishmania major surface protease Gp63 interferes with the function of human monocytes and neutrophils in vitro. Acta Pathologica, Microbiologica et Immunologica Scandinavica 102, 265271.
SUTTERWALA, F. S., NOEL, G. J., CLYNES, R. & MOSSER, D. M. ( 1997). Selective suppression of interleukin-12 induction after macrophage receptor ligation. Journal of Experimental Medicine 185, 19771985.
UZONNA, J. E., JOYCE, K. L. & SCOTT, P. ( 2004). Low dose Leishmania major promotes a transient T helper cell type 2 response that is down-regulated by interferon gamma-producing CD8+ T Cells. Journal of Experimental Medicine 199, 15591566.
VAN ZANDBERGEN, G., KLINGER, M., MUELLER, A., DANNENBERG, S., GEBERT, A., SOLBACH, W. & LASKAY, T. ( 2004). Cutting edge: neutrophil granulocyte serves as a vector for Leishmania entry into macrophages. Journal of Immunology 173, 65216525.
WEI, X. Q., CHARLES, I. G., SMITH, A., URE, J., FENG, G. J., HUANG, F. P., XU, D., MULLER, W., MONCADA, S. & LIEW, F. Y. ( 1995). Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375, 408411.
WEINHEBER, N., WOLFRAM, M., HARBECKE, D. & AEBISCHER, T. ( 1998). Phagocytosis of Leishmania mexicana amastigotes by macrophages leads to a sustained suppression of IL-12 production. European Journal of Immunology 28, 24672477.
WORLD HEALTH ORGANISATION ( 2000). The Leishmaniases and Leishmania/HIV co-infections. WHO Factsheet No. 116. WHO, Geneva.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Parasitology
  • ISSN: 0031-1820
  • EISSN: 1469-8161
  • URL: /core/journals/parasitology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords:

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 8
Total number of PDF views: 60 *
Loading metrics...

Abstract views

Total abstract views: 527 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 21st November 2017. This data will be updated every 24 hours.