|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, Dr. RIVIERE Loïc / SCHEIDIG-BENATAR Christine / ROUX Emeric / HOUSSIN Wendy
Introduction: 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 outmanoeuvre the host defence mechanisms long enough for their progeny to spread. 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. Particular histone modifications are linked to mono-allelic exclusion and epigenetic memory of active var genes. We recently described sumoylation as second post-translational modification playing a role in var gene repression.
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). We investigate whether specific host factors expressed during pregnancy favor switching towards var2CSA. Furthermore, 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. Purified recombinant CSA-binding domains within var2CSA are now being evaluated for the development of a vaccine.
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 show that common and distinct transcriptional control mechanisms exist between rRNA and var gene families. We are now investigating the particular nuclear architecture of rRNA genes.Keywords: paludisme, transport de protéines, variation antigénique, cytoadhérence, telomere
- Freitas-Junior L. H., Hernandez-Rivas R., Ralph S. A., Montiel-Condado D., Ruvalcaba-Salazar O. K., Rojas-Meza A. P., Mâncio-Silva L., Leal-Silvestre R.J., Shorte S. and Scherf A. (2005) Telomeric heterochromatin propagation and histone acetylation control mutually exclusive expression of antigenic variation genes in malaria parasites. Cell 121:25-36. PMID: 15820676
- Duraisingh M.T., Voss T.S., Marty A.J., Duffy M.F.,. Good R.T,. Thompson J.K, Freitas-Junior L.H., Scherf A., Crabb B.S. and Cowman A.F.. (2005) Perinuclear silencing and locus repositioning are linked to regulation of virulence genes in Plasmodium falciparum. Cell 121:13-24. PMID: 15820675
- Ralph SA., Scheidig-Benatar C. and Scherf, A. (2005) Antigenic variation in Plasmodium falciparum is associated with movement of var loci between subnuclear location. PNAS, 102:5414-19. PMID: 15797990
- Viebig N., Gamain B., Scheidig C., Lépolard C., Przyborski J., Lanzer M., Gysin J. and Scherf A. (2005) A single member of the P. falciparum var multi-gene family determines cytoadhesion to the placental receptor CSA. EMBO Rep 6(8):775-81. PMID: 16025132
- . A greedy promoter controls malarial var-iations. 2006 27;124:251-3. PMID: 16439197
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