Lyman Duff Medical Building, McGill University
3775 University St.,
Montreal, QC H3A 2B4
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.
Hugentobler F, Yam KK, Gillard J, Mahbuba R, Olivier M, Cousineau B.
Immunization against Leishmania major Infection Using LACK- and IL-12-Expressing Lactococcus lactis Induces Delay in Footpad Swelling. PLoS One. 2012;7(2):e30945. Epub 2012 Feb 10.
Shio MT, Hassani K, Isnard A, Ralph B, Contreras I, Gomez MA, Abu-Dayyeh I, Olivier M.
Host cell signalling and leishmania mechanisms of evasion. J Trop Med. 2012;2012:819512. Epub 2011 Nov 3.
Kassa FA, Shio MT, Bellemare MJ, Faye B, Ndao M, Olivier M.
New inflammation-related biomarkers during malaria infection. PLoS One. 2011;6(10):e26495. Epub 2011 Oct 20.
Host–pathogen interaction: Culprit within a culprit. Nature. 2011;471:173-174. Epub 2011 March 09.
Hassani K, Antoniak E, Jardim A, Olivier M.
Temperature-induced protein secretion by Leishmania mexicana modulates macrophage signalling and function. PLoS One. 2011 May 3;6(5):e18724.
Yam KK, Hugentobler F, Pouliot P, Stern AM, Lalande JD, Matlashewski G, Olivier M, Cousineau B.
Generation and evaluation of A2-expressing Lactococcus lactis live vaccines against Leishmania donovani in BALB/c mice. J Med Microbiol. 2011 Sep;60(Pt 9):1248-60. Epub 2011 Apr 28.
Jaramillo M, Gomez MA, Larsson O, Shio MT, Topisirovic I, Contreras I, Luxenburg R, Rosenfeld A, Colina R, McMaster RW, Olivier M, Costa-Mattioli M, Sonenberg N.
Leishmania repression of host translation through mTOR cleavage is required for parasite survival and infection. Cell Host Microbe. 2011 Apr 21;9(4):331-41.
Contreras I, Gómez MA, Nguyen O, Shio MT, McMaster RW, Olivier M.
Leishmania-induced inactivation of the macrophage transcription factor AP-1 is mediated by the parasite metalloprotease GP63. PLoS Pathog. 2010 Oct 14;6(10):e1001148.
Shio MT, Kassa FA, Bellemare MJ, Olivier M.
Innate inflammatory response to the malarial pigment hemozoin. Microbes Infect. 2010 Nov;12(12-13):889-99. Epub 2010 Jul 15. Review.