Molecular Mycology - CNRS URA3012  


  HEADDr DROMER Françoise / dromer@pasteur.fr
  MEMBERSANFRY Lucile, BEN ABDALLAH Mariem, Dr BOUKRIS-SITBON Karine, BOUYSSIE Reine, Pr BRETAGNE Stéphane, Dr BUFFET Pierre, Dr DANNAOUI Eric, DESNOS-OLLIVIER Marie, Pr GANTIER Jean-Charles, Dr GARCIA-HERMOSO Dea, HOINARD Damien, Pr LORTHOLARY Olivier, Dr MEMET Sylvie, Dr MORIZOT Gloria, Dr RAMMAERT Blandine, RAOUX-BARBOT Dorothée, STURNY-LECLERE Aude, TOURNAIRE Marc, Frédérique VERNEL-PAUILLAC


  Annual Report

Invasive mycoses represent an important burden in terms of morbidity and mortality. Studying the infection processes contributes to the understanding of the causative agent’s biology and can potentially lead to improved patients’ management. In the field of medical mycology, many aspects of the pathogenic fungi biology and of their interactions with their human or animal hosts are yet to discover.

We are focusing our projects on cryptococcosis. Cryptococcosis is a life-threatening disseminated meningoencephalitis that occurs in up to 18% of patients with AIDS in Africa and South East Asia. The recent estimation by the Center for Diseases Control in the USA suggests that it occurs in nearly 1 million of individuals/year and is associated with more than 600,000 annual deaths. Cryptococcus neoformans is a basidiomycetes surrounded by a capsule identified as the major virulence factor. Our studies combine analysis of the host (clinical and epidemiological studies, animal and cellular models) and the fungus (diversity, variability, virulence) sides. The clinical isolates and the epidemiological data collected at the French National Reference Center for Mycoses and Antifungals provides a means to assess the clinical relevance of the experimental findings.

Molecular basis of idiopathic CD4 lymphocytopenia(ICL) associated with opportunistic fungal infections : (O. Lortholary in collaboration with several groups on the campus and Paris hospitals). Epidemiological studies have emphasized that cryptococcosis is the most frequent opportunistic infection during ICL. We demonstrated that ICL is associated with defective surface expression of CXCR4, a key parameter of lymphocytes homeostasis. We showed that the immune defect can be reversed by IL-2 exposure in vitro using cells from ICL patients and in the corresponding patients after IL-2 treatment with subsequent CD4 lymphocytes recovery.

Study of C. neoformansbiology during infection using clinicalisolates from France(F. Dromer): C. neoformans is a haploid yeast with a bipolar mating system. In addition to asexual multiplication it can have sexual reproduction through "normal" cell fusion with the opposite mating type but also same-sex mating giving rise to a population of haploids, diploids and hybrids. It also exists in 2 varieties neoformans(serotype D) and grubii(serotype A). Very little is known on the population of strains infecting patients in an environment where serotypes A and D coexist. The clinical isolates of C. neoformans var. neoformans and var. grubiirecovered 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 mixed infections exist and if some molecular types are responsible for more severe infections. Interactions of selected molecular types with host cells will be further deciphered.

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 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.

Leishmaniasis(P. Buffet): We have been involved in the set-up of 3 clinical trials on cutaneous leishmaniasis, in collaboration with the Walter reed Army Institute of Research, the Assistance-Publique Hôpitaux de Paris, and the Institut Pasteur in Tunis (Tunisia). We are currently using the database on real-time therapeutic advice to clinicians facing complex decisions that we implemented last year in our collaboration with the National Reference Center for Leishmania (Montpellier). 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 for 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 – co-infections - antibodies - NFKappa B – epidemiology – cryptococcosis – leishmaniasis



  Publications

1. Ben Salah A, Buffet PA, Morizot G, Ben Massoud N, Zaatour A, Ben Alaya N, Haj Hamida NB, El Ahmadi Z, Downs MT, Smith PL, Dellagi K, Grogl M. "WR279,396, a third generation aminoglycoside ointment for the treatment of Leishmania major cutaneous leishmaniasis: a phase 2, randomized, double blind, placebo controlled study." PLoS Negl Trop Dis 2009,3(5): e432.

2. Charlier C, Nielsen K, Daou S, Brigitte M, Chretien F, Dromer F. Evidence for a role of monocytes in dissemination and brain invasion by Cryptococcus Neoformans. Infect Immun, 2009,77:120-127 (selected by the editors of the Journal in the Spotlight of that issue).

3. 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.

4. Garcia-Hermoso D, Hoinard D, Gantier JC, Grenouillet F, Dromer F, Dannaoui E. Molecular and phenotypic evaluation of Lichtheimia corymbifera (formerly Absidia corymbifera) complex isolates associated with human mucormycosis: rehabilitation of L. ramosa. J Clin Microbiol, 2009;47(12):3862-70.

5. Mémet S. NF-kappaB functions in the nervous system: from development to disease. Biochem Pharmacol 2006,72:1180-1195.





Activity Reports 2009 - Institut Pasteur
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