Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production.

Published

Journal Article

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 DeltagliP 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 DeltagliP 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 DeltagliP 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.

Full Text

Duke Authors

Cited Authors

  • Cramer, RA; Gamcsik, MP; Brooking, RM; Najvar, LK; Kirkpatrick, WR; Patterson, TF; Balibar, CJ; Graybill, JR; Perfect, JR; Abraham, SN; Steinbach, WJ

Published Date

  • June 2006

Published In

Volume / Issue

  • 5 / 6

Start / End Page

  • 972 - 980

PubMed ID

  • 16757745

Pubmed Central ID

  • 16757745

International Standard Serial Number (ISSN)

  • 1535-9778

Digital Object Identifier (DOI)

  • 10.1128/EC.00049-06

Language

  • eng

Conference Location

  • United States