Aspergillus Unit
Research activity
Major results
The most important results obtained since the laboratory was created, six years ago, are the following :
Cloning
and molecular analysis of repeated sequences useful for typing strains.
The
first large scale molecular epidemiological study showing the high genetic diversity
of this fungal species and the nosocomial origin of most invasive aspergillosis
infections.
Active
participation in the development of the first commercial ELISA kit based on
the detection of circulating galactomannan for the serological diagnosis of
invasive aspergillosis.
Molecular
characterization of the major antigens of A. fumigatus and discovery
of a new dipeptidylpeptidase activity (DPPV) associated with one of the two
major antigens used for the diagnosis of aspergillosis in the immunocompetent
host.
Cloning
and disruption of a dozen genes encoding putative virulence factors.
Demonstration
of the phagocytosis of conidia by epithelial cells.
analysis
of conidia phagocytosis by the alveolar macrophage.
Induction
of a protective immunity which will result in studies on a possible "vaccination"
against A. fumigatus.
Identification
of the covalent linkages between polysaccharides which form the 3 dimensional
structure of the cell wall and recognition of the central role of a beta1-3/1-6glucans
in the formation of the cell wall; discovery of a beta1-3/1-4glucan for the
first time in fungi.
Molecular analysis of genes responsible for the synthesis of alpha and beta1-3glucans.
Establishment
of an extensive list of enzymes involved in the post synthetic modification
of beta 1-3 glucans with the discovery of a new beta 1-3glucanosyltransferase
activity which plays a role in the morphogenesis of yeast and filamentous fungi.
Demonstration
of the active role of GPI-bound proteins in the biosynthesis of the Aspergillus cell wall.
Research projects
Aspergillus fumigatus is a ubiquitous thermophilic, saprophytic filamentous fungus that disseminates by producing spores that are present in all environments and are continuously inhaled by the humans. For that reason, this mould is responsible for invasive pulmonary diseases, most often fatal among immunocompromized patients. A.fumigatus has become today the major fungal air-borne pathogen in terms of morbidity and mortality in developed countries. The expertise of our unit in biochemistry and molecular biology of A.fumigatus is unique in the world and has allowed to progress significantly in the understanding of the pathology of these threatening infections.
I - A prominent fungal feature : The cell wall
In A.fumigatus, like in other pathogenic fungi, the cell wall is essential for fungal growth as well as for resisting environmental stresses. The cell wall of A.fumigatus is exclusively composed of polysaccharides. The fibrillar core of the A.fumigatus cell wall is basically composed of branched glucan – chitin complex, embedded in an amorphous cement composed of linear chains of α(1-3) (1-4) glucan associated to galactomannan. These two polysaccharides are also major components of the extracellular matrix that hold hyphae together as a biofilm. This biofilm favours growth and increases resistance to antifungals. Organizing the three-dimensional network of polysaccharides responsible for the rigidity of the cell wall is a very complex and sequential enzymatic process. The enzymes involved in the biosynthesis of α and β1-3 glucans, chitin, galactan and N-and O- mannans have been analyzed using genomic and biochemical approaches. The enzymes that are responsible for the branching and cross-linking of the cell wall polysaccharides are also investigated, especially among proteins anchored to plasma membrane by a glycosylphosphatidylinositol moiety.
II - Host pathogen interactions
In collaboration with several other research laboratories, PAMPs and PRRs involved in the immune response of the immunocompetent and immunocompromized mammalian host against A.fumigatus are currently analysed. This approach will open the way to new cellular immunotherapies that are a promising alternative to the poorly efficient antifungal therapies currently available