|Molecular Mycology - CNRS URA3012|
|HEAD||Dr DROMER Françoise / email@example.com|
|MEMBERS||ANFRY Lucile, Dr BOUKRIS-SITBON Karine, BOUYSSIE Reine, Pr BRETAGNE Stéphane, Dr BUFFET Pierre, Dr CHARLIER Caroline, Dr DANNAOUI Eric, DESNOS-OLLIVIER Marie, Pr GANTIER Jean-Charles, Dr GARCIA-HERMOSO Dea, HOINARD Damien, Dr JANBON Guilhem, Pr LORTHOLARY Olivier, Dr MEMET Sylvie, Dr MOGENSEN Estelle, Dr MORIZOT Gloria, MOYRAND Frédérique, PATEL Sweta, Dr RAMMAERT Blandine, RAOUX-BARBOT Dorothée, STURNY-LECLERE Aude, Dr TRIANA Ibelisse, TOURNAIRE Marc
A better understanding of the interactions between hosts and pathogenic fungi should improve the prognosis of fungal infections. Our projects focus on Cryptococcus neoformans and Candida albicans 's pathogenicity by studying the host (clinical and epidemiological studies, animal models) and the fungus (virulence factors, variability) sides, with an efficient interplay between research activities and expertise done at the National Reference Center.
Cryptococcosis is a life-threatening disseminated meningoencephalitis that occurs in up to 18% of patients with AIDS in Africa and South East Asia. C. neoformans is surrounded by a capsule made of polysaccharides, which is a major virulence factor.
C. neoformans crossing of the blood brain barrier (BBB) (F. Dromer): Little is known on the mechanisms allowing C. neoformans to cross the BBB. In collaboration with F. Chrétien (INSERM EMI 0011, Créteil) we are analyzing the mechanisms allowing C. neoformans crossing of the BBB. Using various experimental approaches we have been able to demonstrate the Trojan horse hypothesis for C. neoformans crossing of the BBB, together with other means as free yeasts (transcellular or paracellular passages). We are further analyzing the interactions between C. neoformans and the BBB.
Host response to CNS infection by C. neoformans (S. Mémet): Very few data are available as regards to the role of host cells, namely endothelial and glial cells, in crossing of the BBB, dissemination of C. neoformans, as well as in induction/repression of an inflammatory response. We have therefore initiated a thorough analysis of the inflammatory signalling triggered by C. neoformans, with particular emphasis on the role of the transcription factor NF-B, a major regulator of inflammation, innate and acquired immunity. Experiments are being conducted with two yeasts that induce either a scanty (C. neoformans) or a very strong (C. albicans) inflammatory response. Preliminary results with a human BBB endothelial cell model indicate that although both fungi activate NF-κB in these cells, the time-course of activation is different.
C. neoformans capsule (G. Janbon): Our hypothesis is that in addition to its presence, the variability of the capsule structure should play a role in the yeast's virulence. Genes coding for proteins involved in the biosynthetic pathways of the capsule have been cloned and are studied for their involvement in pathophysiology and for more basic projects (regulation of the nucleotide-sugars transport in the vesicles, relationship between the splicing of some specific genes and the capsule structure…).
Analysis of C. neoformans isolates responsible for infections in France (F. Dromer): The clinical isolates of C. neoformans var. neoformans and var. grubii recovered during a multicenter prospective study in France (CryptoA/D study, 1997-2001) are currently analyzed in terms of serotypes, mating types and genotypes. The objective is to compare this population of isolates with those responsible for infections in other parts of the world, and to analyze whether some molecular types are responsible for more severe infections.
Leishmaniasis (P. Buffet):
We have been involved in the set-up of 3 clinical trials in cutaneous leishmaniasis, in collaboration with the Walter reed Army Insitute of Research, the Assistance-Publique Hôpitaux de Paris, and the Institut Pasteur in Tunis, Tunisia. In the context of our collaboration with the National Reference Center for Leishmania (Montpellier), we set-up a data base on real-time therapeutic advice to clinicians facing complex decisions. We are also collaborating with the Immunophysiology & Intracellular Parasitism Unit (IP) on the evaluation of topical agents' efficacy in experimental cutaneous leishmaniasis.
National Reference Center Mycoses and Antifungals (F. Dromer, O. Lortholary): Our missions include (1) expertise in the identification and characterization of pathogenic fungi and advice for the management of patients with severe mycoses; (2) epidemiological survey of all rare, severe or exotic mycoses as well as of the emergence of resistance to antifungal drugs, with notification through a secured website RESOMYC; (3) design of new typing systems (4) phylogenetic studies.
Keywords: Cryptococcus neoformans – Candida spp. – NFKappa B – Blood-brain barrier – Epidemiology – cryptococcosis – leishmaniasis
1. Desnos-Ollivier M, Bretagne S, Bernede C, Robert V, Raoux D, Chachaty E, Forget E, Lacroix C, Dromer F. Clonal population of flucytosine-resistant Candida tropicalis from blood cultures, Paris, France. Emerg Infect Dis, 2008,14(4):557-565.
Moyrand F, Fontaine T, Janbon G. Systematic capsule gene disruption reveals the central role of galactose metabolism on Cryptococcus neoformans virulence. Mol Microbiol 2007,64:771-781.
. Dromer F, Mathoulin-Pelissier S, Launay O, Lortholary O. Determinants of Disease Presentation and Outcome during Cryptococcosis: The CryptoA/D Study. PLoS Med 2007,4:e21.
. Memet S. NF-kappaB functions in the nervous system: from development to disease. Biochem Pharmacol 2006,72:1180-1195.
5. Charlier C, Chretien F, Baudrimont M, Mordelet E, Lortholary O, Dromer F. Capsule structure changes associated with Cryptococcus neoformans crossing of the blood-brain barrier. Am J Pathol 2005,166:421-432.
Activity Reports 2009 - Institut Pasteur
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