Gliotoxin production in Aspergillus fumigatus contributes to host-specific differences in virulence.
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-kappaB, 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
We deleted 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.
Spikes
Sara
S
Division of Pathology and Laboratory Medicine, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Xu
Ran
R
Nguyen
C Kim
CK
Chamilos
Georgios
G
Kontoyiannis
Dimitrios P
DP
Jacobson
Raymond H
RH
Ejzykowicz
Daniele E
DE
Chiang
Lisa Y
LY
Filler
Scott G
SG
May
Gregory S
GS
D000818:Animals; D001232:Aspergillus fumigatus / Q000145:classification / Q000472:pathogenicity* / Q000502:physiology*; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D004331:Drosophila melanogaster / Q000187:drug effects; D017353:Gene Deletion; D005912:Gliotoxin / Q000096:biosynthesis* / Q000633:toxicity; D008969:Molecular Sequence Data; D014774:Virulence
D017931:DNA Primers; D005912:Gliotoxin