What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus?

Abstract

Gliotoxin is a member of the epipolythiodioxopiperazine class of toxins and is both the major and the most potent toxin produced by Aspergillus fumigatus. Since the discovery of the putative gliotoxin biosynthetic 12-gene cluster in the genome of A. fumigatus, five different laboratories have attempted to determine the role of this toxin in the virulence of A. fumigatus. The genes in the cluster that have been disrupted to study the pathobiological importance of gliotoxin include gliZ that encodes a transcription factor and gliP that encodes a nonribosomal peptide synthase. Two of the five laboratories have reported gliotoxin to be an important virulence determinant of A. fumigatus, while the other three laboratories have shown it to be unimportant. Comparisons of the data generated among the five laboratories revealed that the immunosuppressive regimen used for mice was the key factor that contributed to the observed disparity. Regardless of either the mouse strains used or the route of infection, immunosuppression with a combination of cyclophosphamide and corticosteroids (neutropenic mice) showed gliotoxin to be unimportant. The mice immunosuppressed with corticosteroids alone, however, revealed that gliotoxin is an important virulence determinant of A. fumigatus. These studies indicate that the neutropenic mice model is inadequate to reveal the pathobiological importance of fungal secondary metabolites in invasive pulmonary aspergillosis.

Fig. 1

Genomic organization of the 12 gli-gene cluster responsible for gliotoxin biosynthesis in Aspergillus fumigatus.

Fig. 2

Virulence of the wild type, gliPΔ and reconstituted strains of Aspergillus fumigatus inoculated into two different mouse strains immunosuppressed with cortisone acetate. (A) and (B) Survival of 129/Sv (A) and BALB/c (B) mice infected intranasally with conidia of B-5233, gliPΔ and gliPR (gliPΔ + gliP) strains (from Sugui et al. 2007) [6]. (C) Survival of BALB/c mice infected intranasally with conidia of Af293, gliPΔ and gliPΔ + gliP. (D) Survival of BALB/c mice infected by inhalation of conidia from the strains Af293 and gliP deletant (C and D from Spikes et al. 2008) [4].

Fig. 3

Survival of BALB/c mice infected by inhalation of Af293 and its gli strains. (A) Mice immunosuppressed by combination of cyclophosphamide and cortisone acetate showing no virulence difference between the strains. (B) Mice immunosuppressed by cortisone acetate alone showing statistically significant difference in virulence between the wild type and gliP deletant (from Spikes et al. 2008) [4].

Fig. 4

Toll deficient Drosophila melanogaster infected with Af293 and its derivative gli strains showing attenuated virulence in gliP deletant compared to the wild type and gliP deletant strain reconstituted with the wild type gliP gene (from Spikes et al. 2008) [4].