Fungwall partner1

The fungal cell wall as a target for antifungal therapies

Partner 1

Unité des Aspergillus, Institut Pasteur, Paris (France)

Principal Scientists
Dr Anne Beauvais / Dr Isabelle Mouyna

Other Scientists
Prof. J.P. Latgé - Dr T. Fontaine - Dr N. Fraysse

25, rue du Dr Roux
75724 Paris Cedex 15
+33-1-40613518- +33-1-45688225
fax +33-1-40613419

Experience of the participating organisation and scientists

Participating organisation

The proposed work will be carried out in the Unit of Aspergillus (Institut Pasteur, Paris) that is directed by Prof. J.P. Latgé who is the Co-ordinator of Fungwall.
The focus of the research of the "Aspergillus Unit" is on the biology of Aspergillus fumigatus and the study of invasive aspergillosis, now the most important mould infection worldwide. Expertise relevant for Fungwall is mainly in the fields of fungal protein chemistry, carbohydrate chemistry, genomics and post-genomics. Main achievements include:

The chemical characterization of several cell wall antigens and development of the unique commercially available kit for the detection of invasive aspergillosis based on the detection of a cell wall polysaccharide, the galactomannan;
The cloning and disruption of virulence genes and analysis of pathogenicity in a cellular and murine model of pulmonary aspergillosis;
The structural analysis of the cell wall of A. fumigatus and the characterization of enzymes involved in the cell wall assembly of A. fumigatus.

The Unit has strong interactions with the different technological platforms of the Institute and in particular with Platform 2 of the Genopole, (J.-Y. Coppée) that has lead to the development of DNA arrays for transcript profiling assays integrated in a European project. Proteome analysis, recently undertaken, will benefit from the on-going genome annotation of A. fumigatus to which our laboratory contributes. The Aspergillus Unit has a long-term collaboration with industry in diagnosis and drug development fields. In collaboration with Sanofi-Pasteur, now Bio-Rad, the Aspergillus Unit has played a major role in the characterization of Mabs used for the Aspergillus Platelia® kit for the detection of circulating antigens. A long term collaboration has been established with Aventis for the search of new antifungal drug targets directed towards A. fumigatus.

Participating scientists

All participating scientists, with the exception of JP Latgé, are research associates at the Pasteur Institute. They all have an expertise in fungal cell wall that has been acquired in the last 10 years in this research unit. Recent results of the scientists of the Aspergillus Unit include:

the analysis of the first cell wall transglycosidase ever described (I. Mouyna);
the identification of a common beta 1,3 branched glucan-chitin complex as the common structural core of the cell wall of all fungi that is at the basis of the FungWall proposal (T. Fontaine);
the analysis of alpha and beta 1,3 glucan synthases in A. fumigatus (A. Beauvais);
the analysis of the chitin synthase of A. fumigatus and the characterization of compensatory reactions in the cell wall of chitin synthase mutants (J.P. Latgé);
the differential composition of the surface layer of the conidium and hyphal cell wall (S. Paris);
the identification of cell wall changes in GPI-protein mutants (I. Mouyna);
the characterization of the structure of the GPI-anchor and the understanding of the GPI biosynthesis in A. fumigatus (T. Fontaine).

Drs A. Beauvais and I. Mouyna will be co-principal investigators for Fungwall. Both of them have excellent experience in the molecular analysis of the cell wall genes. They are responsible, with J.P. Latgé for the transcriptome project of A. fumigatus undertaken at Institut Pasteur. S. Paris has the longest experience of the group in A. fumigatus; her role will be essential for the development of new tools in the area as well as for the construction of the numerous mutants that will arise from Fungwall. Another major player will be T. Fontaine who is our carbohydrate chemist who will play an essential role in the analysis of cell wall modifications of the mutants of interest and in the preparation of the substrates for the transglycosidase reaction and analysis of the product.

Relevant publications

Fontaine T., Magnin T., Melhert A., Lamont D., Latgé J.P., Ferguson M.A.J. (2003) Structure of the glycosylphosphatidylinositol membrane anchors from Aspergillus fumigatus membrane proteins. Glycobiology 13:169-177.

Mellado E., Dubreucq G., Mol P., Sarfati J., Paris S., Diaquin M., Holden D.W., Rodriguez-Tudela J.L., Latgé J.P. (2003) Cell wall biogenesis in a double chitin synthase mutant (chsG^-/chsE^-) of Aspergillus fumigatus. Fungal Genet. Biol. 38:98-109.

Beauvais A., Bruneau J.M., Mol P.C., Buitrago M.J., Legrand R., Latgé J.P. (2001) The glucan synthase complex of Aspergillus fumigatus. J. Bacteriol. 183:2273-2279.

Mouyna I,. Fontaine T., Vai M., Monod M., Fonzi W.A., Diaquin M., Popolo L., Hartland R.P., Latgé J.P. (2000) GPI-anchored glucanosyltransferases play an active role in the biosynthesis of the fungal cell wall. J. Biol. Chem. 275:14882-14889.

Fontaine T., Simenel C., Dubreucq G., Adam O., Delepierre M., Lemoine J., Vorgias C.E., Diaquin M., Latgé J.P. (2000) Molecular organization of the alkali-insoluble fraction of Aspergillus fumigatus cell wall. J. Biol. Chem. 275:27594-27607.

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