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Infection and Immunity, December 2006, p. 6761-6768, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00780-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

GliZ, a Transcriptional Regulator of Gliotoxin Biosynthesis, Contributes to Aspergillus fumigatus Virulence{triangledown}

Jin Woo Bok,1 DaWoon Chung,1 S. Arunmozhi Balajee,2 Kieren A. Marr,2,3 David Andes,1 Kristian Fog Nielsen,4 Jens C. Frisvad,4 Katharine A. Kirby,2 and Nancy P. Keller1*

University of Wisconsin—Madison, Madison, Wisconsin,1 Fred Hutchinson Cancer Research Center,2 University of Washington, Seattle, Washington,3 Center for Microbial Biotechnology BioCentrum-DTU, Technical University of Denmark, Lyngby, Denmark4

Received 15 May 2006/ Returned for modification 17 June 2006/ Accepted 16 September 2006

Gliotoxin is a nonribosomal peptide produced by Aspergillus fumigatus. This compound has been proposed as an A. fumigatus virulence factor due to its cytotoxic, genotoxic, and apoptotic properties. Recent identification of the gliotoxin gene cluster identified several genes (gli genes) likely involved in gliotoxin production, including gliZ, encoding a putative Zn2Cys6 binuclear transcription factor. Replacement of gliZ with a marker gene ({Delta}gliZ) resulted in no detectable gliotoxin production and loss of gene expression of other gli cluster genes. Placement of multiple copies of gliZ in the genome increased gliotoxin production. Using endpoint survival data, the {Delta}gliZ and a multiple-copy gliZ strain were not statistically different from the wild type in a murine pulmonary model; however, both the wild-type and the multiple-copy gliZ strain were more virulent than {Delta}laeA (a mutant reduced in production of gliotoxin and other toxins). A flow-cytometric analysis of polymorphonuclear leukocytes (PMNs) exposed to supernatants from wild-type, {Delta}gliZ, complemented {Delta}gliZ, and {Delta}laeA strains supported a role for gliotoxin in apoptotic but not necrotic PMN cell death. This may indicate that several secondary metabolites are involved in A. fumigatus virulence.

* Corresponding author. Mailing address: Department of Plant Pathology, 882 Russell Labs, 1630 Linden Drive, University of Wisconsin—Madison, Madison, WI 53706. Phone: (608) 265-9795. Fax: (608) 263-2626. E-mail: npk{at}plantpath.wisc.edu.

{triangledown} Published ahead of print on 9 October 2006.

Editor: A. Casadevall

Infection and Immunity, December 2006, p. 6761-6768, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00780-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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