Gerald Spaeth
Molecular parasitology and Signaling Unit (ParSig)
Institut Pasteur 25-28 rue du docteur Roux, 75015 Paris
 
Research area of the Unit
 
Our Unit studies virulence mechanisms of the protozoan parasite Leishmania, the etiological agent of leishmaniases, severe human diseases with clinical manifestations ranging from self-curing cutaneous lesions to fatal visceral infection. During the infectious cycle, leishmaniae replicate as extracellular flagellated promastigotes in the midgut of female phlebotomine sand flies. Following transmission during blood feeding, parasites are engulfed by host phagocytes such as macrophages, where they differentiate into non-motile amastigotes that cause the pathology of the disease. Our research program is focused on the functional genetics analysis of parasite-specific signal transduction pathways that sense extracellular cues encountered inside insect and mammalian hosts, and regulate adaptive stage-differentiation required for intracellular infection.
 
Contribution to the programme
 
Our Unit provides important kinomics and phosphoproteomics expertise to the LabEx IBEID. We pursue our established lines of research through three major axes: Axis 1 analyzes the role of Leishmania MAP kinases LmaMPK4, 7, and 10 in environmental sensing, parasite development and pathogenesis utilizing gene knock out and over-expression strategies. Axis 2 applies quantitative and activity-based phospho-proteomics approaches (2D-DiGE, iTRAQ and SILAC LC-MS/MS, 2D in-gel kinase assay) to gain new insight into the post-translational regulation of the Leishmania stress response and to map stress kinase/chaperone substrate relationships. Axis 3 uses next generation sequencing technologies to gain a systems-wide insight into Leishmania virulence regulation through comparative analyses of virulent, hamster-derived and avirulent, culture-derived L. donovani amastigotes. Our program establishes an iterative cycle between kinase discovery and substrate identification that will shed important new light on the signalling pathways that govern Leishmania intracellular survival and pathogenicity.
 
References over the past 5 years
1.        Forestier C.L., Machu C., Loussert C., Pescher P., and Späth G.F., “Imaging host cell-Leishmania interaction dynamics implicates parasite motility, lysosome recruitment and host cell wounding in the infection process”, Cell Host Microbe 2011 Apr 21.
2.        Schmidt-Arras D., Leclercq O., Gherardini P.F., Helmer-Citterich M., Faigle W., Loew D., and Späth G.F., "Adaptation of a 2D in-gel kinase assay to trace phosphotransferase activities in the human pathogen Leishmania donovani”, J Proteomics 2011 Apr 12.
3.        Pescher P., Blisnick T., Bastin P., and Späth G.F., “Quantitative proteome profiling informs on phenotypic traits that adapt Leishmania donovani for axenic and intracellular proliferation”, Cell Microbiol. 2011 Mar 23.
4.        Hem S., Gherardini P.F., Osorio y Fortéa J., Hourdel V., Morales M.A., Watanabe R., Pescher P., Kuzyk M.A., Smith D., Borchers C.H., Zilberstein D., Helmer-Citterich M., Namane A., and Späth G.F., "Identification of Leishmania-specific protein phosphorylation sites by LC-ESI-MS/MS and comparative genomics analyses", Proteomics 2010 Nov 10.
5.        Morales M.A., Watanabe R., Dacher M., Chafey P., Osorio y Fortéa J., Scott D.A., Beverley S.M., Ommen G., Clos J., Hem S., Lenormand P., Rousselle J., Namane A., and Späth G.F., "Phosphoproteome dynamics reveal heat shock protein complexes specific to the Leishmania donovani infectious stage", PNAS 2010,107(18):8381-6.
6.        Morales M.A., Pescher P., Späth G.F., “Leishmania major LmaMPK7 protein kinase activity inhibits intracellular growth of the pathogenic amastigote stage”, Eukaryot Cell. 2010 Jan 9.
7.        Späth G.F., Schlesinger P., Schreiber R., and Beverley S.M., “A novel role for Stat1 in phagosome acidification and natural host resistance to intracellular infection by Leishmania major”, PLoS Pathog. 2009 Apr 5.