Structural Immunology - CNRS URA2185  


  HEADBENTLEY Graham / bentley@pasteur.fr
  MEMBERSDr FAURE Grazyna / Dr GANGNARD Stéphane / Dr JUILLERAT Alexandre
SAUL Frederick / SOUCHON Hélène / Dr VULLIEZ-LE NORMAND Brigitte


  Annual Report

Research themes of the Unit of Structural Immunology centre on the structural and functional characterization of proteins with a biomedical interest. Particular emphasis is given to antigens from infectious agents that are vaccine candidates or targets for drug design. During 2006, we have continued work on antigens from Plasmodium and Shigella flexneri.

Plasmodium antigens

(a) Apical Membrane antigen 1 (AMA1): AMA1, a Plasmodium membrane protein involved in host cell invasion, is a malaria vaccine candidate currently in clinical trials. Following the structure determination of the AMA1 ectoplasmic region and the epitope mapping of an invasion-inhibitory anti-AMA1 monoclonal antibody (mAb) in our unit (Pizarro et al., 2005. Science, 308: 408-11), we have set out to provide a more comprehensive structural analysis of dominant B-cell epitopes that contribute to immune protection. Detailed knowledge of the their location and the presence of polymorphic residues can provide useful information for optimizing AMA1 vaccine constructs. To this end, we have determined structure of an AMA1-antibody complex, and crystallographic analysis of other such complexes is currently in progress (Figure 1).

(b) P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1): PfEMP1 forms a family of variant parasite adhesion proteins expressed on the surface of infected erythrocytes. These are complex multi-domain proteins that cause cyto-adhesion of infected erythrocytes in diverse tissues and organs. We are studying two PfEMP1 variants implicated in severe malaria: one causing rosetting (adhesion of infected erythrocytes to healthy erythrocytes), the other causing sequestration of infected erythrocytes in the placenta. We have expressed individual domains of these two PfEMP1 variants and have identified those that are directly involved in adhesion. In addition, we have made quantitative receptor-binding studies in the case of the placental variant, which binds to chondroitin sulphate proteoglycans. We have antibodies that inhibit receptor binding in each case.

Shigellosis vaccine development

The O-antigen polysaccharide of LPS is a major determinant of immune protection against Shigella flexneri. To contribute towards the development of effective shigellosis vaccines, we have determined the structure of a protecting anti-O-antigen mAb in complex with a synthetic O-antigen oligosaccharide and as a cross-reaction complex with an affinity-selected peptide. The peptide was shown to be a structural mimic of the saccharide epitope.

bentley.jpg

Figure 1. Structure de la région ectoplasmique d'AMA1 de Plasmodium vivax (cyan) liée au Fab d'un anticorps spécifique (chaîne légère en orange, chaîne lourde en mauve).

Figure 1. Structure of the ectoplasmic region of AMA1 from Plasmodium vivax (ribbon representation, cyan) bound to the Fab fragment of a specific mAb (molecular surface representation, light chain in orange, heavy chain in mauve).



  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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