海角社区

Focus

Immune evasion by parasites:

Integrity of IFN-gamma-induced signaling pathway (e.g. JAK2-STAT1alpha) 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. 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. We recently reported that the IFN-gamma-inducible JAK2-STAT1alpha 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/macrophage 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 macrophage dysfunctions and in installation and propagation of this parasite within its host. In parallel, we performed experiments representing the first demonstration that signaling inhibitors such as the PTPs inhibitors peroxovanadium compounds represent potential new therapic agents to modulate host immune response favoring a better control over different types of infection including leishmaniasis. Our present interest is to further our investigations to discover other negative regulatory mechanisms (e.g. Proteasome, phosphatases, surface receptors) modulated by Leishmania or other pathogens (Mycobacteria, Trypanosoma, Malaria, HCV) 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.

Malaria pigment (hemozoin) and inflammatory response:

Plasmodium falciparum, the causative agent of malaria, is one of the major killer of the infectious world affecting over 200 million people with more than 2 million death per year in tropical and sub-tropical area of the world. Of interest, we recently reported that hemozoin -an inert metabolic waste produced by plasmodium-digested hemoglobin and released in circulation while erythrocytes lysed- is avidly engulfed by macrophages bringing about their activation and released of inflammatory molecules (eg Chemokines, MRPs, IFN-gamma-induced nitric oxide). As nitric oxide and chemokines have been reported to play a critical role in development of some pathological events related to malaria infection, hemozoin in this context seems to play an unexpected role. Undertanding about signaling mechanisms regulating these cellular modulation may permit to better monitor inflammatory events that are detrimental for the host as it can favor the development important malaria pathologies such as cerebral malaria, hepatosplenomegaly and anemia.

Keywords

Host-Pathogen Interaction, Macrophage, Mycobacteria, Leishmania, Malaria, Inflammation, Cell Signaling, Protein Tyrosine Phosphatase, Subversion Mechanism, Exosome

Selected Publications

S. Vidal, M.L. Tremblay, G. Govoni, S. Gauthier, G. Sebastiani, D. Malo, E. Skamene,听M. Olivier, S. Jotly, and P. Gros.听 The Ity/Lsh/Bcg locus:听 Natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 驳别苍别.听Journal of Experimental Medecine,听 182: 655-666 (1995).

M. Olivier, P. Cook, J. DeSanctis, Z. Hel, W. Wojciechowski, N.E. Reiner, E. Skamene and D. Radzioch.听 Phenotypic difference between Bcgr听补苍诲 Bcgs macrophages is related to differences in protein-kinase-C-dependent signalling. 听European Journal of Biochemistry , 251: 734-743 (1998).

M. Olivier, B.J. Romero-Gallo, C. Matte, J. Blanchette, B.I. Posner, M. Tremblay and R. Faure.听 Modulation of interferon-g-induced macrophage activation by phosphotyrosine phosphatases inhibition.听 Effect on murine leishmaniasis progression.听Journal of Biological Chemistry , 273: 13944-13949 (1998).

M. Rojas, M. Olivier, P. Gros, L.F. Barrera and L.F. Garcia.听 TNF-a and IL-10 modulate the induction of apoptosis by virulent Mycobacterium tuberculosis in murine macrophages.听Journal of Immunology听 162: 6122-6131 (1999).

M. Rojas, L.F. Garcia,J. Nigou, G. Puzo and M. Olivier.听 Mannosylated lipoarabinomannan antagonizes Mycobacterium tuberculosis-induced macrophage apoptosis by altering Ca2+-dependent cell signaling. Journal of Infectious Diseases 182: 240-251 (2000).

M. Rojas, M. Olivier and L.F. Garcia.听 Activation of JAK2/STAT1-dependent signaling events during Mycobacterium tuberculosis -induced macrophage apoptosis.听Cellular Immunology听 217: 58-66 (2002).

I. Abu Dayyeh, M. Tiemi Shio, S. Sato, S. Akira, B. Cousineau and M. Olivier.听Leishmania induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif.听PLoS Neglected Tropical Diseases听 2(12): e305听 (2008). 听听听 听听听(Selected as Featured article)

M.A. Gomez, I. Contreras, M. Halle, M.L. Tremblay, R.W. McMaster and M. Olivier. The major surface protease of Leishmania is implicated in the modulation of macrophage protein tyrosine phosphatases.听Science Signaling听听 2 (90), ra58. Pages 1-12 (2009).听听 (Faculty of 1000; Must read (6.0))听 IF:20, 2012

M.T. Shio, S.C. Eisenbarth, M. Saravia, M.-J. Bellemare, A. Vinet, K.W. Harder, S. Sutterwala, D.S. Bohle, A. Descoteaux, R.A. Flavell and M. Olivier.听 Malarial pigment-induced NLRP3 inflammasome activation depends on Lyn and Syk kinases. PLoS Pathogens听 E-pub Aug 21;听 5(8):e1000559 (2009). (Selected as Featured Article)

I. Contreras-Garcia, M.A. Gomez, O. Nguyen, M.T. Shio, R.W. McMaster and M. Olivier.听Leishmania-induced inactivation of the macrophage transcription factor AP-1 is mediated by the parasite metalloprotease GP63.听PLoS Pathogens听 E-pub Oct 15th (2010).

M. Olivier.听 Host-Pathogen Interaction听: Culprit within a culprit.听Nature听471: 173-174听 (2011). K.听

Hassani, E. Antoniak, A. Jardim and M. Olivier.听 Temperature-induced protein secretion by Leishmania mexicana modulates macrophage signaling and function.听PLoS ONE听听2011 May 3;6(5):e18724.

M. Jaramillo, M.A. Gomez, O. Larsson, M.T. Shio, I. Toposorovic, I. Contreras, R. Luxenburg, A. Rosenfeld, R. Colina, R.W. McMaster, M. Olivier*, M. Costa-Mattioli* and N. Sonenberg*.听Leishmania repression of host translation through mTOR cleavage is required for parasite survival and infection.听Cell Host & Microbes听 9(4):331-41 (2011). 听 听听* Equal co-corresponding authors.

F.A. Kassa, M.T. Shio, M.-J. Bellemare, M. Ndao and M. Olivier. Identification of New Inflammation-Related Biomarkers During Malaria.听PLoS ONE听 听2011;6(10):e26495.

K. Hassani and M. Olivier.听 Immunomodulatory impact of Leishmania-induced exosomes: A comparative proteomic and functional analyses. PLoS Neglected Tropical Diseases 2013 May 2;7(5):e2185.

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