Eukaryotic Cell
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Eukaryotic Cell, September 2007, p. 1562-1569, Vol. 6, No. 9
1535-9778/07/$08.00+0     doi:10.1128/EC.00141-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Gliotoxin Is a Virulence Factor of Aspergillus fumigatus: gliP Deletion Attenuates Virulence in Mice Immunosuppressed with Hydrocortisone{triangledown}

Janyce A. Sugui,1,{dagger} Julian Pardo,2,{dagger} Yun C. Chang,1 Kol A. Zarember,3 Glenn Nardone,4 Eva M. Galvez,5 Arno Müllbacher,6 John I. Gallin,3 Markus M. Simon,2 and Kyung J. Kwon-Chung1*

Laboratory of Clinical Infectious Diseases,1 Laboratory of Host Defense,3 Research Technology Branch, National Institutes of Health, Bethesda, Maryland,4 Max-Planck-Institute for Immunology, Freiburg, Germany,2 Institut für Physikalische Chemie, Freiburg Universität, Freiburg, Germany,5 John Curtin School of Medical Research, Australian National University, Canberra, Australia6

Received 24 April 2007/ Accepted 23 June 2007

Gliotoxin is an immunosuppressive mycotoxin long suspected to be a potential virulence factor of Aspergillus fumigatus. Recent studies using mutants lacking gliotoxin production, however, suggested that the mycotoxin is not important for pathogenesis of A. fumigatus in neutropenic mice resulting from treatment with cyclophosphomide and hydrocortisone. In this study, we report on the pathobiological role of gliotoxin in two different mouse strains, 129/Sv and BALB/c, that were immunosuppressed by hydrocortisone alone to avoid neutropenia. These strains of mice were infected using the isogenic set of a wild type strain (B-5233) and its mutant strain (gliP{Delta}) and the the glip reconstituted strain (gliPR). The gliP gene encodes a nonribosomal peptide synthase that catalyzes the first step in gliotoxin biosynthesis. The gliP{Delta} strain was significantly less virulent than strain B-5233 or gliPR in both mouse models. In vitro assays with culture filtrates (CFs) of B-5233, gliP{Delta}, and gliPR strains showed the following: (i) deletion of gliP abrogated gliotoxin production, as determined by high-performance liquid chromatography analysis; (ii) unlike the CFs from strains B-5233 and gliPR, gliP{Delta} CFs failed to induce proapoptotic processes in EL4 thymoma cells, as tested by Bak conformational change, mitochondrial-membrane potential disruption, superoxide production, caspase 3 activation, and phosphatidylserine translocation. Furthermore, superoxide production in human neutrophils was strongly inhibited by CFs from strain B-5233 and the gliPR strain, but not the gliP{Delta} strain. Our study confirms that gliotoxin is an important virulence determinant of A. fumigatus and that the type of immunosuppression regimen used is important to reveal the pathogenic potential of gliotoxin.

* Corresponding author. Mailing address: Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. Phone: (301) 496-1602. Fax: (301) 480-3240. E-mail: june_kwon-chung{at}nih.gov

{triangledown} Published ahead of print on 29 June 2007.

{dagger} J.A.S. and J.P. contributed equally to this study.

Eukaryotic Cell, September 2007, p. 1562-1569, Vol. 6, No. 9
1535-9778/07/$08.00+0     doi:10.1128/EC.00141-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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