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Eukaryotic Cell, August 2008, p. 1268-1277, Vol. 7, No. 8
1535-9778/08/$08.00+0     doi:10.1128/EC.00109-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Contribution of Galactofuranose to the Virulence of the Opportunistic Pathogen Aspergillus fumigatus{triangledown}

Philipp S. Schmalhorst,1 Sven Krappmann,2,{dagger} Wouter Vervecken,3 Manfred Rohde,4 Meike Müller,5 Gerhard H. Braus,2 Roland Contreras,3 Armin Braun,5 Hans Bakker,1 and Françoise H. Routier1*

Department of Cellular Chemistry, Hannover Medical School, Hannover, Germany,1 Department of Molecular Microbiology and Genetics, Georg August University, Göttingen, Germany,2 Department of Molecular Biology, Ghent University, and Department for Molecular Biomedical Research, VIB, Ghent, Belgium,3 Department of Microbial Pathogenicity, Helmholtz Centre for Infection Research, Braunschweig, Germany,4 Department of Immunology, Allergology and Immunotoxicology, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany5

Received 27 March 2008/ Accepted 9 June 2008

The filamentous fungus Aspergillus fumigatus is responsible for a lethal disease called invasive aspergillosis that affects immunocompromised patients. This disease, like other human fungal diseases, is generally treated by compounds targeting the primary fungal cell membrane sterol. Recently, glucan synthesis inhibitors were added to the limited antifungal arsenal and encouraged the search for novel targets in cell wall biosynthesis. Although galactomannan is a major component of the A. fumigatus cell wall and extracellular matrix, the biosynthesis and role of galactomannan are currently unknown. By a targeted gene deletion approach, we demonstrate that UDP-galactopyranose mutase, a key enzyme of galactofuranose metabolism, controls the biosynthesis of galactomannan and galactofuranose containing glycoconjugates. The glfA deletion mutant generated in this study is devoid of galactofuranose and displays attenuated virulence in a low-dose mouse model of invasive aspergillosis that likely reflects the impaired growth of the mutant at mammalian body temperature. Furthermore, the absence of galactofuranose results in a thinner cell wall that correlates with an increased susceptibility to several antifungal agents. The UDP-galactopyranose mutase thus appears to be an appealing adjunct therapeutic target in combination with other drugs against A. fumigatus. Its absence from mammalian cells indeed offers a considerable advantage to achieve therapeutic selectivity.

* Corresponding author. Mailing address: Department of Cellular Chemistry (OE 4330), Hannover Medical School, 30625 Hannover, Germany. Phone: 49 (511) 532-9807. Fax: 49 (511) 532-3956. E-mail: Routier.Francoise{at}mh-hannover.de

{triangledown} Published ahead of print on 13 June 2008.

{dagger} Present address: Research Center for Infectious Diseases, Würzburg, Germany.

Eukaryotic Cell, August 2008, p. 1268-1277, Vol. 7, No. 8
1535-9778/08/$08.00+0     doi:10.1128/EC.00109-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Engel, J., Schmalhorst, P. S., Dork-Bousset, T., Ferrieres, V., Routier, F. H. (2009). A Single UDP-galactofuranose Transporter Is Required for Galactofuranosylation in Aspergillus fumigatus. J. Biol. Chem. 284: 33859-33868 [Abstract] [Full Text]  
  • Dumestre-Perard, C., Lamy, B., Aldebert, D., Lemaire-Vieille, C., Grillot, R., Brion, J.-P., Gagnon, J., Cesbron, J.-Y. (2008). Aspergillus Conidia Activate the Complement by the Mannan-Binding Lectin C2 Bypass Mechanism. J. Immunol. 181: 7100-7105 [Abstract] [Full Text]  


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