Immune evasion by parasites; Leishmania topoisomerase and apoptosis
Lyman Duff Medical Building
3775 University St., Room 610
Montreal, QC H3A 2B4
Tel: (514) 398-5592
Fax: (514) 398-7052
martin [dot] olivier [at] mcgill [dot] ca (Email)
Integrity of IFN?-induced signaling pathway (e.g. JAK2-STAT1a) regulating immune functions such as IL-12, MHC class I and II, is primordial for the development of effective host protection against infections involving protozoan parasites of Leishmania genus. Importance of cytokines in the control of Leishmania donovani (Ld) infection is well established. However, once mononuclear phagocytes become infected with Ld several important macrophage functions involved in innate protection (e.g. Nitric oxide, oxygen radicals) and in the development of protective immune responses (e.g. IL-12 secretion, antigen processing and presentation through MHC class I and II) are inactivated to some extent.
Several years ago, we started to obtain evidence demonstrating that signaling events being dependent upon Ca2+- and protein kinase C (PKC) were altered in Ld-infected human monocytes and that such inactivation could at least in part explain some of the phagocyte functions inhibition observed during leishmaniasis.
More recently, we reported that the IFN?-inducible JAK2-STAT1a pathway was abnormal in Leishmania-infected cells. We further highlighted the importance of PTP SHP-1 in JAK2 inactivation that we showed to be rapidly triggered following parasite/MØ interaction. In vitro and in vivo experiments performed with mice being deficient for the PTP SHP-1 have permitted to firmly establish that the PTP SHP-1 plays a pivotal role in Ld-induced MØ dysfunctions and in installation and propagation of this parasite within its host. Of importance, we showed that the development of cutaneous leishmaniasis was completely abolished in absence of SHP-1.
In view of these findings, we performed experiments revealing that peroxovanadium (pV)-mediated modulation of PTP activities in vivo was a very effective way to completely block the progression of murine visceral and cutaneous leishmaniasis. We also obtained clear evidence supporting the pivotal role played by NO in this pV treatment having shown powerful anti-leishmania effect. These experiments represent the first demonstration that signaling inhibitors such as the pV compounds could be potentially used in therapy to modulate host immune response favoring a better control over different types of infection.
We are presently pursuing investigations to discover other negative regulatory events (e.g. Proteasome, phosphatases, surface receptors) modulated by Leishmania or other pathogens to subvert the innate immune response of the host and thus favoring pathogens installment and propagation. A better understanding of these mechanisms could conduct to the development of new therapy to control infectious agents. Similarly, the study of the regulation of macrophage functions and Leishmania replication (contact M. Olivier for more information) could lead to the discovery a cellular targets for new drug development.
Selected Recent Publications
M. A. Gomez, I. Contreras, M. Hallé, M. L. Tremblay, R. W. McMaster, M. Olivier, Leishmania GP63 Alters Host Signaling Through Cleavage-Activated Protein Tyrosine Phosphatases. Sci. Signal. 2, ra58 (2009).Summary Abstract
M. Olivier, J. Badaro, F.J. Medrano, J. Moreno. Cellular and molecular events during Leishmania/HIV pathogenesis. (In press in Transactions of the Royal Society of Tropical Medicine and Hygiene).
Blanchette J, Jaramillo M, Olivier M. "Signalling events involved in interferon-gamma-inducible macrophage nitric oxide generation." Immunology 108(4):513-22 (2003)
J.F. Marquis, M. Drolet and M. Olivier. Consequence of Hoechst 33342-mediated Leishmania DNA topoisomerase-I inhibition on parasite replication. Parasitology 126(Pt 1):21-30 (2003)
M. Jaramillo and M. Olivier. "Hydrogen peroxide induces murine macrophage chemokine gene transcription via extracellular signal-regulated kinase- and cyclic adenosine 5'-monophosphate (cAMP)-dependent pathways: involvement of NF-kappa B, activator protein 1, and cAMP response element binding protein." Journal of Immunology 169(12):7026-38 (2002)
N. Dumais, S. Bounou, M. Olivier and M. Tremblay. "Prostaglandin E2—mediated activation of HIV-1 long terminal repeat transcription in human T cells necessitates CCAAT/enhancer binding protein (C/EBP) binding sites in addition to cooperative interactions between C/EBPß and cyclic adenosine 5'-monophosphate response element binding protein". Journal of Immunology 168: 274-282 (2002).
C. Matte and M. Olivier. "Leishmania-induced cellular recruitment during early inflammatory response: Modulation of pro-inflammatory cytokines and chemokines." Journal of Infectious Diseases 185 (5): 673-681 (2002).
G. Forget, K.A. Siminovitch, S. Brochu, S. Rivest, D. Radzioch and M. Olivier. "Role of host phosphotyrosine phosphatase SHP-1 in the development of murine leishmaniasis." European Journal of Immunology 31: 3185-3196 (2001).
J. Celli, M. Olivier and B.B. Finlay. "Inhibition of PI3-kinase by enteropathogenic Escherichia coli mediates antiphagocytosis". EMBO Journal 20: 1245-1258 (2001).
C. Matte, G. Maion, W. Mourad and M. Olivier. "Leishmania donovani-induced macrophages cyclooxygenase-2 and prostaglandin E2 synthesis." Parasite Immunology 23: 1-9 (2001).
G. Roy, C. Dumas, D. Sereno, Y. Wu, A.K. Singh, M.J. Tremblay, M. Ouellette, M. Olivier and B. Papadopoulou. "Episomal and stable expression of the luciferase reporter gene for quantifying Leishmania spp. infections in macrophages and in animals models." Molecular and Biochemical Parasitology 110: 195-206 (2000).
C. Matte, J.F. Marquis, J. Blanchette, P. Gros, B.I. Posner, R. Faure and M. Olivier. "Peroxovanadium-mediated protection against murine leishmaniasis: role of the modulation of nitric oxide." European Journal of Immunology 30: 2555-2564 (2000).
M. Rojas, L.F. Garcia,J. Nigou, G. Puzo and M. Olivier. "Mannosylated lipoarabinomannan antagonizes Mycobacterium tuberculosis-induced macrophage apoptosis by altering Ca2+-dependent cell signaling." Journal of Infectious Diseases 182: 240-251 (2000).
J. Blanchette, N. Racette, R. Faure, K.A. Siminovitch and M. Olivier. "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 (11): 3737-3744 (1999).
S. Broccoli, J.F. Marquis, B. Papadopoulou, M. Olivier and M. Drolet. "Characterization of a Leishmania donovani gene encoding a protein resembles a type IB topoisomerase." Nucleic Acid Research 27: 2745-2752 (1999).
M. Olivier, B.J. Romero-Gallo, C. Matte, J. Blanchette, B.I. Posner, M. Tremblay and R. Faure. "Modulation of interferon-?-induced macrophage activation by phosphhotyrosine phosphatases inhibition. Effect on murine leishmaniasis progression." Journal of Biological Chemistry, 273: 13944-13949 (1998).
M. Olivier, P. Cook, J. DeSanctis, Z. Hel, W. Wojciechowski, N.E. Reiner, E. Skamene and D. Radzioch. "Phenotypic difference between Bcgr and Bcgs macrophages is related to differences in protein-kinase-C-dependent signalling." European Journal of Biochemistry, 251: 734-743 (1998).
R. Bernier, B. Barbeau, M. Tremblay and M. Olivier. "The lipophosphoglycan of Leishmania donovani can up-regulates HIV-1 transcription in T cells through the Nuclear Factor-?B elements." Journal of Immunology, 160: 2881-2888 (1998).
C. Dumas, M. Ouellette, J. Tovar, M.L. Cunningham, A.H. Fairlamb, S. Tamar, M. Olivier and B. Papadopoulou. "Disruption of the trypanothione gene decreases the ability of Leishmania to survive oxidative stress in macrophages." EMBO Journal, 16: 2590-2598 (1997).
S. Vidal, M.L. Tremblay, G. Govoni, S. Gauthier, G. Sebastiani, D. Malo, E. Skamene, M. Olivier, S. Jotly, and P. Gros. "The Ity/Lsh/Bcg locus: Natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene." Journal of Experimental Medecine, 182: 655-666 (1995).
M. Olivier, R.W. Brownsey and N.E. Reiner. "Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation of protein kinase C." Proceeding of the National Academy of Sciences (USA), 89: 7481-7485 (1992).
M. Olivier, K.G. Baimbridge and N.E. Reiner. "Stimulus-response coupling in monocytes infected with Leishmania: Inhibition of N-formyl-methionyl-leucyl-phenylalanine-induced stimulus-response coupling in monocytes infected with Leishmania: evidence for a defect in agonist-induced calcium release." Journal of Immunology, 148: 1188-1196 (1992).