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Bok JW, Chung D, Balajee SA, Marr KA, Andes D, Nielsen KF,
Frisvad JC, Kirby KA, Keller NP.
GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to
Aspergillus fumigatus virulence.
Infect Immun.
2006 Oct 9
Department of Plant Pathology, University of Wisconsin-Madison, 882 Russell
Labs, 1630 Linden Drive, Madison, WI 53706, USA.
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 Zn(2)Cys(6) binuclear
transcription factor. Replacement of gliZ with a marker gene (DeltagliZ)
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 DeltagliZ 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 DeltalaeA (a mutant reduced in production of
gliotoxin and other toxins). A flow-cytometric analysis of polymorphonuclear
leukocytes (PMNs) exposed to supernatants from wild-type, DeltagliZ,
complemented DeltagliZ, and DeltalaeA 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.
PMID: 17030582 |
