|Parasite Virulence - CNRS URA2581, INSERM Avenir|
|HEAD||Dr SPAETH Gerald / firstname.lastname@example.org|
|MEMBERS||Dr FORESTIER Claire / Dr MORALES Miguel
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. We are using a phospho-proteomic approach to identify LmaMPK substrates and to gain insight into novel amastigote-specific signal transduction pathways implicated in parasite development. To date, 50 distinct phosphoproteins have been identified including 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.
|Publications 2006 of the unit on Pasteur's references database|
Activity Reports 2006 - Institut Pasteur
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