Integrative Biology of Emerging Infectious Diseases (IBEID) / Principal investigators
Parasite Molecular Immunology Unit
Institut Pasteur 25-28 rue du docteur Roux, 75015 Paris
Research area of the Unit
Our activities, centered on malaria pathophysiology and anti-malarials, articulate laboratory investigations with studies in malaria-endemic areas. We investigate how membrane remodeling by Plasmodium falciparum impacts on host erythrocyte deformability, allows intra-erythrocytic stages to withstand exposure to febrile temperatures and modulates clearance by the spleen. We explore rosetting, a faciparum virulence factor, analysethe repertoire of rosette-forming adhesins and study the functional and serologic impact of their polymorphism. We dissect the molecular interactions with erythrocyte surface receptors during P. faciparum rosetting and during P. vivax erythrocyte invasion. Work on antimalarials includes analysis of P. falciparum gene flows in endemic areas, investigation of the molecular and cellular mechanisms implicated in artemisinin resistance that is emerging in Cambodia. In parallel, we conduct a drug discovery project, which targets a novel calls of parasite enzyme implicated in a critical step of the erythrocytic cycle. Current projects focus on the hit to lead generation and molecular drug-target investigations.
Contribution to the programme
Our contribution to the programme mainly concerns drug resistance and development of novel antimalarials. Current work on drug resistance is conducted in collaboration with D Ménards'group at IP Cambodia and aims at identifying the cellular events associated with reduced susceptibility to artemisinins that has spread across Western Cambodia. We have identified the developmental stage implicated and designed a new drug susceptibility assay. We are working at developing methods allowing to separate susceptible from resistant parasite sub-populations in field isolates. With the PF1 Génomique Platform of the Génopole, we have undertaken, a whole genome analysis of parasite isolates using NGS to identify the causative genetic changes in resistant parasites. Our drug lead optimisation project involving biochemical and biological validation of the inhibitors is conducted in the frame of an ANR RPIB contract with Sanofi. We investigate the structural basis of the inhibition and the role of the target enzymes at different stages of the life cycle of the parasite using reverse genetic and chemobiological approaches.
References over the past 5 years
1. Safeukui I, Correas JM, Brousse V, Hirt D, Deplaine G, Mulé S, Lesurtel M, Goasguen N, Sauvanet A, Couvelard A, Kerneis S, Khun H, Vigan-Womas I, Ottone C, Molina TJ, Tréluyer JM, Mercereau-Puijalon O, Milon G, David PH, Buffet PA. Retention of Plasmodium falciparum ring-infected erythrocytes in the slow, open microcirculation of the human spleen. Blood. 2008 Sep 15;112(6):2520-8. PMID: 18579796
2. Vigan-Womas I, Guillotte M, Le Scanf C, Igonet S, Petres S, Juillerat A, Badaut C, Nato F, Schneider A, Lavergne A, Contamin H, Tall A, Baril L, Bentley GA, Mercereau-Puijalon O. An in vivo and in vitro model of Plasmodium falciparum rosetting and autoagglutination mediated by varO, a group A var gene encoding a frequent serotype. Infect Immun. 2008 Dec;76(12):5565-80. Epub 2008 Sep 22. PMID: 18809668
3. Ménard D, Barnadas C, Bouchier C, Henry-Halldin C, Gray R, Ratsimbasoa A, Thonier V, Carod J-F, Domarle O, Colin Y, Bertrand O, Picot J, King CL, Grimberg BT, Mercereau-Puijalon O, Zimmerman PA. Plasmodium vivax Clinical Malaria is Commonly Observed in Duffy-negative Malagasy People. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5967-71. PMID: 2023143
4. Deplaine G, Lavazec C, Bischoff E, Natalang O, Perrot S, Guillotte-Blisnick M, Coppée JY, Mercereau-Puijalon O, David PH. Tolerance to artesunate in transgenic Plasmodium falciparum parasites over-expressing a tryptophan rich protein. Antimicrob Agents Chemother. 2011 Jun;55(6):2576-84. Epub 2011 Apr 4. PMID: 21464256
5. Trape JF, Tall A, Diagne N, Ndiath O, Ly AB, Faye J, Dieye-Ba F, Roucher C, Bouganali C, Badiane A, Diene Sarr F, Mazenot C, Touré-Baldé A, Raoult D, Druilhe P, Mercereau-Puijalon O, Rogier C, Sokhna C. Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study. Lancet Infect Dis. 2011 Lancet Infect Dis. 2011 Dec;11(12):925-32. Epub 2011 Aug 17. PMID: 2185623
6. Legrand E, Yrinesi J, Ekala, M-T Péneau J, Volney B, Berger F, Bouchier C, Bertani S, Musset L, Meynard J-B, Mercereau-Puijalon O. Discordant temporal evolution of Pfcrt and Pfmdr1 genotypes and Plasmodium falciparum in vitro drug susceptibility to 4-aminoquinolines after changing drug policy in French Guiana. Antimicrob Agents Chemother. 2012 Mar;56(3):1382-9.
7. Vigan-Womas I, Guillotte M, Juillerat A, Hessel A, Raynal B, England P, Cohen JJ, Bertrand O, Peyrard T, Bentley GA, Lewit-Bentley A, Mercereau-Puijalon O, Structural basis for the ABO blood-group dependence of Plasmodium falciparum rosetting. PloS Pathogens in press