Biomedical Parasitology


  HEADDr DRUILHE Pierre / druilhe@pasteur.fr
  MEMBERSDr ANDERSEN Claire / CHIMMA Pattamawan / DAHER Lena / DEMANGA Corine
Dr DEROUBAIX-HEZ Stéphanie / Dr JAFARSHAD Ali / MEJIA Pedro / Dr PERIGNON
Dr PERLAZA Blanca Liliana / Dr PRIEUR Eric / Dr ROUSSILHON Christian / Dr SAUZET Jean-Pierre


  Annual Report

Introduction: The focus of our Unit is to analyze the natural history of human-P.falciparum (P.f) immune interactions. Our goals are a) to provide knowledge about various factors that modulate this interaction towards either susceptibility or resistance, and b) to employ this knowledge in order to manipulate identified mechanisms to the benefit of human kind, while establishing continuity between research, antigen discovery, and product development. To this end we rely on a) the general advances in biology, b) the development of parasite-specific tools, and c) clinical investigations (as the human-P.f interaction is unique).

Vaccine Development: In 2006 we have invested much effort in obtaining a clinical proof of concept of our lab results by implementing four vaccine trials at Phase I and IIb i.e. involving a parasite challenge.

Asexual Blood Stages: Results from a total of 15 studies have now converged in support of the vaccine potential of Merozoite Surface Protein 3 (MSP3). For instance, the presence of IgG3 anti-MSP3 was found to reduce by three-fold the number of malaria attacks over the ensuing six years in children exposed to a natural challenge every two days. We have produced a therapeutic human anti-MSP3 mAb and tested it in the chimpanzee. We have characterized a MSP3 multigene family, sharing three B-cell epitopes, that are fully conserved in all isolates tested. We have characterized the molecular events leading to MN-dependant Ab-mediated parasite killing, showing that it requires the co-activation of FcγRII and RIII, only hormonal concentrations of Ab (700pM), and is triggered by soluble Ag, leading us to uncover a new subset of the genome ripe for vaccine discovery.

We have confirmed that co-infection with worms increases malaria attacks by 60-400% and acts by inducing a Th2 bias to anti-malaria immune responses, suggesting that deworming could lead to the rapid acquisition of protection.

We have used a reverse genetics approach combined with structural predictions to discover 12 novel P.f Ags targeted by Abs mediating parasite-killing.

Liver Stages (LS): We capitalized on our major improvement of culture output to elucidate the LS transcriptome and to use an immuno-proteomic approach to the discovery of novel protective Ags.

We have characterized a novel Ag, SR11.1, that induces protection against P. yoelii challenge in mice and against P.f in primates.

We have collaborated with industry to demonstrate that a novel anti-malarial compound had a 10E5 greater effect upon LS than existing compounds.

We have capitalized on our technique of intra-hepatic epitope-specific T-cell recruitment to show that in situ cell responses were inversely correlated with peripheral blood responses.

Based on knowledge acquired with our P.f-Human RBC-SCID model, we have developed a human Hepatocyte-SCID mouse model and demonstrated its functionality e.g. by receptivity to P.f sporozoite invasion and LS development.

druilhe.jpg

Figure: P.f Liver Schizonts in Hu-Hep-Scid a new model for human malaria and hepatitis B and C.



  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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