Hostname: page-component-78c5997874-s2hrs Total loading time: 0 Render date: 2024-11-05T15:32:18.097Z Has data issue: false hasContentIssue false

Subversion of host cell signalling by the protozoan parasite Leishmania

Published online by Cambridge University Press:  11 November 2005

D. J. GREGORY
Affiliation:
Centre for the Study of Host Resistance at the Research Institute of the McGill University Health Centre, and Departments of Microbiology and Immunology, McGill University, Montréal, Québec, Canada
M. OLIVIER
Affiliation:
Centre for the Study of Host Resistance at the Research Institute of the McGill University Health Centre, and Departments of Microbiology and Immunology, McGill University, Montréal, Québec, Canada Experimental Medicine, McGill University, Montréal, Québec, Canada

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.

Type
Research Article
Copyright
© 2005 Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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.Google Scholar
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, 13891400.3.0.CO;2-1>CrossRefGoogle Scholar
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.Google Scholar
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.Google Scholar
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, 37373744.3.0.CO;2-S>CrossRefGoogle Scholar
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.Google Scholar
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.Google Scholar
BUCHMULLER-ROUILLER, Y. & MAUEL, J. ( 1987). Impairment of macrophage oxidative-metabolism by Leishmania. Experientia 43, 665665.Google Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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, 762773.3.0.CO;2-4>CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
DESCOTEAUX, A. & MATLASHEWSKI, G. ( 1989). c-fos and tumor necrosis factor gene expression in Leishmania donovani-infected macrophages. Molecular Cell Biology 9, 52235227.CrossRefGoogle Scholar
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.Google Scholar
DESCOTEAUX, A. & TURCO, S. J. ( 1999). Glycoconjugates in Leishmania infectivity. Biochimica et Biophysica Acta 1455, 341352.CrossRefGoogle Scholar
DESJEUX, P. ( 2004). Leishmaniasis. Nature Reviews Microbiology 2, 692.CrossRefGoogle Scholar
EILAM, Y., EL ON, J. & SPIRA, D. T. ( 1985). Leishmania major: excreted factor, calcium ions, and the survival of amastigotes. Experimental Parasitology 59, 161168.CrossRefGoogle Scholar
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, 31853196.3.0.CO;2-J>CrossRefGoogle Scholar
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.Google Scholar
FRUTH, U., SOLIOZ, N. & LOUIS, J. A. ( 1993). Leishmania major interferes with antigen presentation by infected macrophages. Journal of Immunology 150, 18571864.Google Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
HERWALDT, B. L. ( 1999). Leishmaniasis. Lancet 354, 11911199.CrossRefGoogle Scholar
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.Google Scholar
JUNGHAE, M. & RAYNES, J. G. ( 2002). Activation of p38 mitogen-activated protein kinase attenuates Leishmania donovani infection in macrophages. Infection and Immunity 70, 50265035.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
KANE, M. M. & MOSSER, D. M. ( 2000). Leishmania parasites and their ploys to disrupt macrophage activation. Current Opinion in Hematology 7, 2631.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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.CrossRef
MARTH, T. & KELSALL, B. L. ( 1997). Regulation of interleukin-12 by complement receptor 3 signaling. Journal of Experimental Medicine 185, 19871995.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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, 25552564.3.0.CO;2-X>CrossRefGoogle Scholar
MATTE, C. & OLIVIER, M. ( 2002). Leishmania-induced cellular recruitment during the early inflammatory response: modulation of proinflammatory mediators. Journal of Infectious Disease 185, 673681.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.Google Scholar
NANDAN, D. & REINER, N. E. ( 2005). Leishmania donovani engages in regulatory interference by targeting macrophage protein tyrosine phosphatase SHP-1. Clinical Immunology 114, 266277.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
OLIVIER, M. ( 1996). Modulation of host cell intracellular Ca2+. Parasitology Today 12, 145150.CrossRefGoogle Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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, 235244.3.0.CO;2-S>CrossRefGoogle Scholar
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.Google Scholar
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, 22352244.3.0.CO;2-9>CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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, 24672477.3.0.CO;2-1>CrossRefGoogle Scholar
WORLD HEALTH ORGANISATION ( 2000). The Leishmaniases and Leishmania/HIV co-infections. WHO Factsheet No. 116. WHO, Geneva.