|Parasite Virulence - INSERM Avenir, CNRS URA2581|
|HEAD||SPAETH, Gerald / email@example.com|
|MEMBERS||Dr. FORESTIER, Claire / Dr. MORALES, Miguel / Dr. SCHMIDT-ARRAS, Dirk / Mme PESCHER, Pascale / Mme WATANABE, Reiko
M. GUESNON, Mickael / M. YAU, Wai-Lok / Mlle ABDERRHAHIM, Amal
Our laboratory use genetic, proteomic and immunological methods to study the molecular basis of virulence and persistence of Leishmania, an important human pathogen, which produces serious diseases world wide. The projects are aimed to identify and validate target molecules for the development of novel anti-leishmanial strategies.
Leishmania signaling pathways implicated in pathogenicity. Leishmania undergoes multiple differentiation steps in response to extracellular signals that adapt parasite virulence for survival in the insect vector and the human host. We use gene knock out and over-expression strategies to elucidate the role of the Leishmania extracellular-regulated/mitogen activated protein kinases LmaMPK4, 7, and 10 in parasite environmental sensing. Utilizing epitope-tagged recombinant kinases expressed in transgenic parasites we could reveal the cytoplasmic localization of these proteins, their amastigote-specific phosphorylation and activity, and their interaction with members of the heat shock protein family. By using a phospho-proteomic 2D-DIGE approach we identified potential LmaMPK7 substrates and gained insight into novel amastigote-specific signal transduction pathways implicated in parasite development. 75 distinct phosphoproteins have been identified and quantified across the parasite stages. We revealed multiple homologs of RNA helicases, RNA binding proteins, and protein chaperones. These phospho-proteins may be implicated in regulating Leishmania gene expression, which occurs by mechanisms that are distinct from the human host and rely on poly-cistronic transcription, trans-splicing, and differential RNA and protein stability.
Interaction of Leishmania glycolipid virulence factors with host immunity. Leishmania surface glycoconjugates are important virulence determinants with highly unique structures that are recognized by pathways of innate immunity and may stimulate immune protection. We previously identified the major surface glycoconjugate LPG as the first bona fide Leishmania glycolipid antigen and showed that a subset of highly liver-enriched “innate-like” lymphocytes, Natural Killer T (NK T) cells, participate in the early inflammatory response to visceral L.donovani infection. Our current efforts are focused on the characterization and isolation of Leishmania-responsive NKT cell subsets, the analysis of LPG intracellular trafficking in infected host cells, and its potential processing in the endo-lysosomal compartment. We will combine molecular genetics and immunological approaches and utilize glycolipid-deficient Leishmania mutants that express truncated forms of LPG to correlate in situ specific epitopes with LPG immune-recognition and -protection.
Keywords: Leishmania, virulence, signaling, MAP kinases
Morales M.A., Watanabe R., Laurent C., Lenormand P., Rousselle J.C., Namane A. and G.F. Späth, 2007, “Phosphoproteomic analysis of Leishmania donovani pro- and amastigote stages”, Proteomics, 2008 18:350-363.
Morales M.A., Renaud O., Faigle W., Shorte S.L. and G. F. Späth, 2007, “ Over-expression of Leishmania major MAP kinases reveals stage-specific induction of phosphotransferase activity”, Int. J. of Parasitology, , 11:1187-99.
Arevalo I, Tulliano G, Quispe A, Spaeth G, Matlashewski, G Llanos-Cuentas A, Pollack H, 2007, “Role of imiquimod and parenteral meglumine antimoniate in the initial treatment of cutaneous leishmaniasis”, Clin. Infect. Dis., 44:1549-54.
Amprey J.L., Im J.S., Turco S.J., Murray H.W., Illarionov P.A., Besra G.S., Porcelli S.A., and G. F. Späth, 2004, “Innate recognition of Leishmania donovani glycolipids by CD1d-restricted T cells induces an early protective immune response during liver infection”, J. Exp.Med., Oct 4;200(7):895-904.
Späth G.F., Lye L.F. and S.M. Beverley, “Identification of a compensatory mutant (lpg2-REV) in Leishmania major able to survive as amastigotes within macrophages without LPG2-dependent glycoconjugates, and its significance to virulence and immunization strategies”, Infection & Immunity, 2004 72:3622-7.
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Activity Reports 2007 - Institut Pasteur
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