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Eukaryotic Cell, June 2006, p. 972-980, Vol. 5, No. 6
1535-9778/06/$08.00+0     doi:10.1128/EC.00049-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Disruption of a Nonribosomal Peptide Synthetase in Aspergillus fumigatus Eliminates Gliotoxin Production

Robert A. Cramer Jr.,1* Michael P. Gamcsik,2 Rhea M. Brooking,3 Laura K. Najvar,4 William R. Kirkpatrick,4 Thomas F. Patterson,4 Carl J. Balibar,5 John R. Graybill,4 John R. Perfect,1,6 Soman N. Abraham,1,3 and William J. Steinbach1,7

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710,1 Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina 27710,2 Department of Pathology, Duke University, Durham, North Carolina 27710,3 Department of Medicine, Division of Infectious Disease, The University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229,4 Department of Biological Chemistry and Molecular Pharmacology, Harvard University Medical School, Boston, Massachusetts 02115,5 Department of Medicine, Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina 27710,6 Department of Pediatrics, Division of Pediatric Infectious Disease, Duke University Medical Center, Durham, North Carolina 277107

Received 16 February 2006/ Accepted 20 April 2006

The fungal secondary metabolite gliotoxin produced by Aspergillus fumigatus has been hypothesized to be important in the development of invasive aspergillosis. In this study, we addressed this hypothesis by disrupting a nonribosomal peptide synthetase (NRPS) (encoded by gliP) predicted to be involved in gliotoxin production. Mutants with a disrupted gliP locus failed to produce gliotoxin, which confirmed the role of the NRPS encoded by gliP in gliotoxin biosynthesis. We found no morphological, developmental, or physiological defects in {Delta}gliP mutant strains. In addition, disruption of gliP resulted in down regulation of gene expression in the gliotoxin biosynthesis gene cluster, which was restored with addition of exogenous gliotoxin. This interesting result suggests a role for gliotoxin in regulating its own production. Culture filtrates from the {Delta}gliP mutant were unable to inhibit ionomycin-dependent degranulation of mast cells, suggesting a role for gliotoxin in suppressing mast cell degranulation and possibly in disease development. However, the {Delta}gliP mutant did not have an impact on survival or tissue burden in a murine inhalational model of invasive aspergillosis. This result suggests that gliotoxin is not required for virulence in an immunosuppressed host with an invasive pulmonary infection.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710. Phone: (919) 681-2613. Fax: (919) 684-8902. E-mail: rcramer{at}duke.edu.

Eukaryotic Cell, June 2006, p. 972-980, Vol. 5, No. 6
1535-9778/06/$08.00+0     doi:10.1128/EC.00049-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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