Gliotoxin Production in Aspergillus fumigatus Contributes to Host-Specific Differences in Virulence

S Spikes, R Xu, CK Nguyen, G Chamilos… - The Journal of …, 2008 - academic.oup.com
S Spikes, R Xu, CK Nguyen, G Chamilos, DP Kontoyiannis, RH Jacobson, DE Ejzykowicz…
The Journal of infectious diseases, 2008academic.oup.com
Background. Gliotoxin is a epipolythiodioxopiperazine toxin that is made by the filamentous
fungus Aspergillus fumigatus. Gliotoxin has a wide range of effects on metazoan cells in
culture, including induction of apoptosis through inhibition of Nf-κB, and inhibition of
superoxide production by phagocytes. These activities have led to the proposal that gliotoxin
contributes to pathogenesis during invasive aspergillosis. We tested this hypothesis by
creating isogenic strains of gliotoxin-producing and nonproducing strains. Methods …
Abstract
Background. Gliotoxin is a epipolythiodioxopiperazine toxin that is made by the filamentous fungus Aspergillus fumigatus. Gliotoxin has a wide range of effects on metazoan cells in culture, including induction of apoptosis through inhibition of Nf-κB, and inhibition of superoxide production by phagocytes. These activities have led to the proposal that gliotoxin contributes to pathogenesis during invasive aspergillosis. We tested this hypothesis by creating isogenic strains of gliotoxin-producing and nonproducing strains.
Methods. Wedeleted gliP, the gene that encodes the nonribosomal peptide synthetase GliP. gliP catalyzes the first biosynthetic step in the synthesis of gliotoxin. We then tested for gliotoxin production and virulence in different animal models.
Results. Deletion of gliP resulted in strains that were wild type for growth, but they did not synthesize gliotoxin. Transformation of gliP deletion mutants with a full copy of gliP restored gliotoxin production. The gliP deletion strain had attenuated virulence in nonneutropenic mice immunosuppressed with corticosteroids, but had normal virulence in neutropenic mice. It also had reduced virulence in a Drosophila melanogaster model.
Conclusions. Gliotoxin only contributes to the virulence of A. fumigatus in nonneutropenic mice and in fruit flies with functional phagocytes. These results suggest that the principal targets of gliotoxin are neutrophils or other phagocytes.
Oxford University Press