|Biology of Host-Parasite Interactions - CNRS URA2581|
|HEAD||Prof. SCHERF Artur / email@example.com|
|MEMBERS||Dr ANTIA Meher / Dr COELHO NUNES Marta / Dr FERNANDEZ Pablo / Dr GAMAIN Benoit
ISSAR Neha / Dr LOPEZ-RUBIO José Juan / MANCIO DA SILVA Liliana / Dr MATTEI Denise / Dr OKADA Mami / Dr VIEBIG Nicola
The laboratory focuses on strategies that enable the human protozoan pathogen Plasmodium falciparum to survive in the hostile environment of the human host and establish chronic infection.
1. Molecular mechanisms of antigenic variation.
Antigenic Variation is a strategy employed by malaria species to outmaneuver the host defense mechanisms long enough for their progeny to spread. We have established that distinct epigenetic factors control the molecular process of antigenic variation. Mutually exclusive expression of a single member of a multigene family (called var gene family) leads to the successive expression of variant molecules on the surface of infected erythrocytes. A subtelomeric non-coding element called rep20 is a critical DNA region involved in cluster formation between chromosome ends and acts as a sink for a number of chromatin silencing factors such as PfSir2. We demonstrated that a “telomere position effect”-like mechanism brings about repression of antigenic variation genes located near telomere repeats. Another epigenetic factor associated with var gene activation is the relocation of a silent var gene into a peri-nuclear region compatible with transcription. We focus now on histone marks that determine mono-allelic exclusion and epigenetic memory of active var genes.
2. Cytoadhesion and malaria pathogenesis. Parasite-encoded virulence factors (adhesion molecules) are inserted into the erythrocyte membrane during intracellular blood stage development. We focus on host–parasite interactions during pregnancy-associated malaria (PAM) in order to identify the optimal surface antigens for inclusion in a vaccine that could prevent malaria during pregnancy. We have identified the parasite ligand, which mediates binding to the major placental receptor (Chondroitin sulfate A, CSA), called var2CSA. Var2CSA disruptant mutants do not recover the CSA binding phenotype, demonstrating that no other parasite gene can compensate for the loss of function. CSA-binding domains within var2CSA were identified and are now being evaluated for the development of a vaccine. Furthermore, we investigate whether signal transduction is involved in var gene switching.
3. Intracellular trafficking.
We investigate mutant parasites that have a defect in IE adhesion to endothelial cells. The analysis of mutant parasite lines that have deleted a chromosome region including the clag9 gene, revealed that parasites express a member of the var gene family at the surface of IE but these IEs are unable to adhere to common adhesion receptors (CD36, ICAM-1, CSA etc.). Our data indicate that clag9 is not itself an adhesion molecule but is crucial for the correct assembly of the adhesive complex at the IE surface.
4. Epigenetic control of differential transcription of rRNA genes.
P. falciparum has a low copy number of rRNA units, which are distributed on different chromosomes and are differentially expressed. All rRNA genes are clustered in the nucleolus of the parasite. We investigate common and distinct transcriptional control mechanisms between rRNA and var gene families.
|Publications 2006 of the unit on Pasteur's references database|
Activity Reports 2006 - Institut Pasteur
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