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Infection and Immunity, March 2007, p. 1237-1244, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01416-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Aspergillus fumigatus Does Not Require Fatty Acid Metabolism via Isocitrate Lyase for Development of Invasive Aspergillosis{triangledown}

Felicitas Schöbel,1 Oumaïma Ibrahim-Granet,2 Patrick Avé,3 Jean-Paul Latgé,2 Axel A. Brakhage,1 and Matthias Brock1*

Leibniz Institute for Natural Product Research and Infection Biology (HKI) and Friedrich-Schiller University Jena, Beutenbergstr. 11a, 07745 Jena, Germany,1 Aspergillus Unit, Institut Pasteur, 25 Rue du Dr. Roux, 75724 Paris, France,2 Histopathology Unit, Institut Pasteur, 25 Rue du Dr. Roux, 75724 Paris, France3

Received 3 September 2006/ Returned for modification 10 October 2006/ Accepted 10 December 2006

Aspergillus fumigatus is the most prevalent airborne filamentous fungus causing invasive aspergillosis in immunocompromised individuals. Only a limited number of determinants directly associated with virulence are known, and the metabolic requirements of the fungus to grow inside a host have not yet been investigated. Previous studies on pathogenic microorganisms, i.e., the bacterium Mycobacterium tuberculosis and the yeast Candida albicans, have revealed an essential role for isocitrate lyase in pathogenicity. In this study, we generated an isocitrate lyase deletion strain to test whether this strain shows attenuation in virulence. Results have revealed that isocitrate lyase from A. fumigatus is not required for the development of invasive aspergillosis. In a murine model of invasive aspergillosis, the wild-type strain, an isocitrate lyase deletion strain, and a complemented mutant strain were similarly effective in killing mice. Moreover, thin sections demonstrated invasive growth of all strains. Additionally, thin sections of lung tissue from patients with invasive aspergillosis stained with anti-isocitrate lyase antibodies remained negative. From these results, we cannot exclude the use of lipids or fatty acids as a carbon source for A. fumigatus during invasive growth. Nevertheless, test results do imply that the glyoxylate cycle from A. fumigatus is not required for the anaplerotic synthesis of oxaloacetate under infectious conditions. Therefore, an antifungal drug inhibiting fungal isocitrate lyases, postulated to act against Candida infections, is assumed to be ineffective against A. fumigatus.

* Corresponding author. Mailing address: Leibniz Institute for Natural Products Research and Infection Biology, Beutenbergstr. 11a, 07745 Jena, Germany. Phone: 49 (0)3641 656865. Fax: 49 (0)3641 656825. E-mail: Matthias.brock{at}hki-jena.de.

{triangledown} Published ahead of print on 18 December 2006.

Editor: A. Casadevall

Infection and Immunity, March 2007, p. 1237-1244, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01416-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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