|Biology of Host-Parasite Interactions - CNRS URA2581|
|HEAD||Prof. Artur SCHERF / firstname.lastname@example.org|
|MEMBERS||Dr. Arnaud CHENE / Aurélie CLAES / Anne COZANET / Dr. Pablo FERNANDEZ / Dr. Benoît GAMAIN / Eeshita GHOSH DASTIDAR / Dr. Jürg GYSIN / Dr. José-Juan LOPEZ RUBIO / Dr. Nicholas MALMQUIST / Cédric MATHIEU / Dr. Denise MATTEI / Dr. Salah MECHERI / Roger PERONET / Stéphane PETRES / Hiroshi SAKAMOTO / Christine SCHEIDIG-BENATAR / Dr. Nicolai SIEGEL / Dr. Anand SRIVASTAVA / Dr. Qingfeng ZHANG
Introduction: The laboratory focuses on strategies that enable the human protozoan pathogen Plasmodium falciparumto survive in the hostile environment of the human host and establish chronic blood stage infection.
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. Subtelomeric non-coding elements are critical DNA regions involved in cluster formation between chromosome ends and bind a number of chromatin silencing factors such as PfSir2. These Perinuclear Repressive Centers are crucial for the control of the silent state of antigenic variation genes, whose members locate to the perinuclear space. Another epigenetic factor associated with var gene activation is the relocation of a silent var gene into a particular peri-nuclear region compatible with transcription. We identified several histone modifications that are linked to mono-allelic exclusion and epigenetic memory of active var genes. Sumoylation of PfSir2 was discovered in our laboratory and we explore its role in gene regulation.
Cytoadhesion and malaria pathogenesis. Parasite-encoded virulence factors 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 present during pregnancy favour expression of var2CSA, which mediates the CSA adhesion phenotype. 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 var2CSA domains are now being evaluated for the development of a vaccine. We have obtained expression of a full-length molecule and adhesion-blocking antibodies from animals immunized with distinct var2CSA domains. Our research aims to develop a recombinant vaccine being able to protect pregnant women from malaria disease.
Intracellular trafficking. We investigate mutant parasites that have a defect in infected erythrocyte (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.
Expression and spatial organisation of rRNA genes. P. falciparum has a low copy number of rRNA units, which are, unlike other rDNA genes, distributed on different chromosomes and are differentially expressed. We found that all rRNA genes are clustered in the nucleolus independent of their transcriptional state. In addition, common and distinct transcriptional control mechanisms exist between rRNA and var gene families. We are now investigating the factors that determine the particular perinuclear spatial organisation of rRNA genes and their differential expression.
Pathogenesis of experimental cerebral malaria (CM). The group of S. Mecheri (E3 attached to BIHP since 2008) has identified a new mechanism by which histamine, a vaso-active amine, plays an essential role in the pathogenesis of experimental CM (P. berghei/mouse system) via two main receptors H1R and H2R, expressed essentially in peripheral tissues. This group has pursued his studies by investigating the contribution to malaria pathogenesis of H3R, a histamine receptor mainly expressed in the brain and endowed with inhibitory functions on histamine release and synthesis in this tissue. Accordingly, by using H3R-deficient mice, it was recently demonstrated that histamine signaling in the brain has a protective effect against CM. These findings led to the design of a novel therapeutic approach using H3R agonists and H1R and H2R antagonists to alleviate symptoms of CM.
P. falciparum Transfection Platform (under the responsibility of H. Sakamoto, attached to BIHP since 2008). It is specialized in the construction of transfection plasmids for different research purposes for the malaria groups working on P. falciparum in the Department of Parasitology and Mycology.
Keywords: Malaria, Antigenic variation, Protein Trafficking, Cytoadhesion, Telomere
Issar, N., Roux, E., Mattei, D. and Scherf A. (2008) Investigation of sumoylation in malaria parasites. Cell. Microbiology. Jun 10. 1999-2011
Scherf, A., Rivière, L., Lopez-Rubio, JJ. (2008) SnapShot: Var gene expression in the malaria parasite. Cell 11;134(1):190
Beghdadi W, Porcherie A, Schneider BS, Dubayle D, Peronet R, Huerre M, Watanabe T, Ohtsu H, Louis J, Mécheri S.(2008) Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease.J Exp Med. Feb 18;205(2):395-408.
Tonkin CJ, Carret CK, Duraisingh MT, Voss TS, Ralph SA, Hommel M, Duffy MF, Silva LM, Scherf A, Ivens A, Speed TP, Beeson JG, Cowman AF.(2009) Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in Plasmodium falciparum.PLoS Biol. Apr 14;7(4)
Lopez-Rubio JJ, Mancio-Silva L, Scherf A.(2009) Genome-wide analysis of heterochromatin associates clonally variant gene regulation with perinuclear repressive centers in malaria parasites.Cell Host Microbe. 19;5(2):179-90.
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