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  Aspergil


  Director : LATGE Jean-Paul (jplatge@pasteur.fr)


  abstract

 

Aspergillus fumigatus is a thermophilic, saprophytic filamentous fungus that sporulates abundantly in nature. Pulmonary diseases consecutive to the inhalation of airborne conidia of A. fumigatus are often fatal among immunocompromised patients. Indeed, A. fumigatus has become today the most important fungal aerial pathogen in developed countries. The first research theme of the laboratory is medically orientated and is focused on the study of invasive aspergillosis. The other research area is more fundamental and concerns the study of the fungal cell wall biosynthesis that is a key morphogenetic event in the fungal life.



  report

cale

I - Pathobiology of Aspergillus fumigatus

Pathobiological mechanisms responsible for the establishment of A. fumigatus in the lung parenchyma are investigated. The interactions between the alveolar macrophage (AM) that is the main phagocytic cells of the lung environment and the conidia of A. fumigatus have been studied (Granet, Philippe). The phagocytic events have been characterized using human or mouse cells from resistant imunocompetent mice and susceptible transgenic or cortisone treated animals. Actin plays an essential role in the early step of the internalization of conidia by AM ; the conidia are then quickly addressed to the phagolysosome. Intramacrophagic killing of the conidia is extremely slow and is associated to the production of reactive oxygen intermediates and the acidification of the phagolysosome. Conidial killing is highly reduced by glucocorticoids.

A transcriptome/proteome analysis of genes and proteins expressed during the early stages of the infection has been started in collaboration with the GMP Laboratory and use wild-type and mutant strains with different levels of virulence under growth conditions mimicking the environment encountered by A. fumigatus in the lung (Buitrago).

Previous molecular investigations have not identified a specific virulence factor essential for mycelial growth in vivo. In contrast, recent studies using mutants affected in the conidial cell wall have shown that the pathogenicity of A. fumigatus is associated at least partly to resistance against the host defence mechanisms that fail to eliminate the conidia(Paris, Chabane).

II - Structural characterization and biosynthesis of the cell wall of A. fumigatus

Major polysaccharides of the cell wall of A. fumigatus are a and ß(1-3) glucans. Biosynthesis of ß(1-3) glucans is under the control of a membrane protein complex, the glucan synthase. This complex is composed of 2 essential members, Rho1p, a regulatory GTPase and FKSp, the putative catalytic subunit using UDP-glucose as the substrate. Both genes are essential for A. fumigatus. Three AGS genes involved in the biosynthesis of a (1-3) glucans have been identified and the AGS mutants are characterized by a reduced growth and altered conidiation (Beauvais).

In the periplasmic space, neosynthesized ß1-3 glucans are modified and associated to the other cell wall polysaccharides to produce the rigid three-dimensional network characteristic of the cell wall. Chemical characterization of the A. fumigatus cell wall has shown that the central core of the cell wall is a branched ß1-3/1-6 glucan to which are attached chitin and galactomannan (Fontaine). Such organization requires the presence of active glucanosyltransferases in the periplasmic space. During the search for such activities, it was shown for the first time that glycosyltransferases bound to the membrane by a glycosylphosphatidyl inositol (GPI) anchor play a major role in the biosynthesis of the yeast and mold cell wall (Mouyna). Chemical characterization of the GPI anchor and its biosynthesis in A. fumigatus has been studied (Fontaine). A dozen of GPI-anchored proteins, common to both filamentous fungi and yeast have been identified following a proteome and comparative genomic analysis of GPI-anchored proteins of S. cerevisiae and A. fumigatus that was made possible following the recent sequencing of the genome of A. fumigatus. Their role in the biosynthesis of the A. fumigatus cell wall is presently investigated using a combination of molecular biology, carbohydrate and protein chemistry techniques (Bernard, Chabane, Mouyna).

The biosynthesis of galactomannan is also investigated. Such study is specially interesting in A. fumigatus to understand both the structural organization of the cell wall but also to identify protein glycosylation pathways specific to filamentous fungi since we have identified for the first time in A. fumigatus a N-glycan with a branched mannose structure decorated with terminal non-reducing galactofuranose on a secreted phospholipase C (Buitrago).



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  publications

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  personnel

  Office staff Researchers Scientific trainees Other personnel
 

CORMIER Marinette (mcormier@pasteur.fr)

BEAUVAIS Anne, IP (Researcher, abeauvai@pasteur.fr)

FONTAINE Thierry, IP (Researcher, tfontaine@pasteur.fr)

GRANET Oumaïma, IP (Researcher, ogranet@pasteur.fr)

MOUYNA Isabelle, IP (Researcher, imouyna@pasteur.fr)

PARIS Sophie, IP (Researcher, sparis@pasteur.fr)

BERNARD Muriel (PhD student, mbernard@pasteur.fr)

BUITRAGO Maria José (Postdoc, buitrago@pasteur.fr)

CHABANE Sandrine (Postdoc, schabane@pasteur.fr)

COSTACHEL Corina (Postdoc, ccostach@pasteur.fr)

PHILIPPE Bruno (PhD student, bphil@pasteur.fr)

DEBEAUPUIS Jean-Paul, INSERM (Engineer, jpdbp@pasteur.fr)

DIAQUIN Michel, IP (Technician)

SARFATI jacqueline, INSERM (Engineer, jsarfati@pasteur.fr)


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