GliZ, a Transcriptional Regulator of Gliotoxin Biosynthesis, Contributes toAspergillus fumigatusVirulence

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Gliotoxin is a nonribosomal peptide produced byAspergillus fumigatus. This compound has been proposed as anA. fumigatusvirulence factor due to its cytotoxic, genotoxic, and apoptotic properties. Recent identification of the gliotoxin gene cluster identified several genes (gligenes) likely involved in gliotoxin production, includinggliZ, encoding a putative Zn2Cys6binuclear transcription factor. Replacement ofgliZwith a marker gene (ΔgliZ) resulted in no detectable gliotoxin production and loss of gene expression of otherglicluster genes. Placement of multiple copies ofgliZin the genome increased gliotoxin production. Using endpoint survival data, theΔgliZand a multiple-copygliZstrain were not statistically different from the wild type in a murine pulmonary model; however, both the wild-type and the multiple-copygliZstrain were more virulent thanΔlaeA(a mutant reduced in production of gliotoxin and other toxins). A flow-cytometric analysis of polymorphonuclear leukocytes (PMNs) exposed to supernatants from wild-type,ΔgliZ, complementedΔgliZ, andΔlaeAstrains supported a role for gliotoxin in apoptotic but not necrotic PMN cell death. This may indicate that several secondary metabolites are involved inA. fumigatusvirulence.