|Parasite Molecular Immunology - CNRS URA2581|
|HEAD||Dr MERCEREAU-PUIJALON Odile / firstname.lastname@example.org|
|MEMBERS||Dr BARALE Jean-Christophe / Dr BONNEFOY Serge / Dr BUFFET Pierre / Dr DAVID Peter
DEPLAINE Guillaume / Dr FANDEUR Thierry / Dr LAVAZEC Catherine / Dr MORIZOT Gloria
NATALANG Onguma / Dr SAFEUKUI Innocent / Dr VIGAN Inès
Focused on Plasmodium falciparum blood stages, our approach integrates identification of parasite virulence factors, disease mechanisms and field studies, with the aim of developing new intervention tools, including improved therapy.
Drug therapy and resistance
With the Institut Pasteur Network, we established a coordinated programme on drug resistance in the field. We reported the first cases of in vitro resistance to artemether, associated with a specific mutation in the target enzyme, the SERCA-PfATPase6 . The impact of controlled drug intake over 10 years was retrospectively studied in Dielmo, Senegal. Invasion by drug-resistant alleles occurred within a few hundred chloroquine or SP treatment courses. Thus, proper use of antimalarials did not deter spreading of resistance, favored by frequent post-treatment reinfections. This is highly relevant to drug-combination implementation policies .
SUB2 is a subtilisin-like protease involved in the maturation of merozoite surface proteins MSP1 and AMA1, a processing conserved across Plasmodium species. Current efforts on the characterization of the catalytic properties of SUB2 and the selection PfSUB2-specific inhibitors led us to establish the proof of concept that SUB2 is a promising target for new anti-malarial drugs.
Parasite virulence factors & disease mechanisms:
During invasion of the red blood cell (RBC), the Ring Erythrocyte Surface Antigen (PfRESA) is inserted beneath the RBC membrane where it interacts with spectrin. Loss of RESA expression resulted in an increased susceptibility of the infected RBCs to febrile temperatures . Isolation of a resa1-KO and its isogenic revertant led us to show that PfRESA contributed to additional physiological alterations of the RBC membrane at the ring stage.
Such alterations play a role in the spleen-processing of P. falciparum infected RBCs, which includes parasite elimination and modulation of the parasite phenotype. We have established an experimental isolated-perfused human spleens system, functionally validated by the efficient processing of artesunate-treated infected RBCs . Handling of live infected RBC is under study to determine the respective contribution of mechanical versus immunological factors to parasite clearance.
Severe malaria in African children is associated with parasitized RBCs which can bind uninfected RBCs (“rosetting”) or other infected RBCs ("auto-agglutination »). The varO adhesin mediates both cytoadherence types. Field studies highlighted a remarkably elevated seroprevalence, indicating that varO is a "common" serotype. VarO rosetting involves a novel parasite/receptor interaction. The recombinant rosette-mediating domain induced high titers of surface-reacting and rosette-disrupting antibodies. These data qualify varO as an interesting intervention target.
Comparison of the transcriptome of parasites from patients ex vivo and after long-term culture identified genes only expressed in vivo. Some code for proteins with an export motif to the erythrocyte membrane. Their contribution to remodeling this key interface with the host is under study.
|Publications 2006 of the unit on Pasteur's references database|
Activity Reports 2006 - Institut Pasteur
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