Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone


Sugui JA, Pardo J, Chang YC, Zarember KA, Nardone G, Galvez EM, Müllbacher A, Gallin JI, Simon MM, Kwon-Chung KJ
Eukaryot Cell. 2007 Sep;6(9):1562-9


Gliotoxin is an immunosuppressive mycotoxin long suspected to be a potential virulence factor of Aspergillus fumigatus (AF). Recent studies using mutants lacking gliotoxin production, however, suggested that the mycotoxin is not important for pathogenesis of AF in neutropenic mice resulting from the treatment with cyclophosphomide and hydrocortisone. In this study, we report on the pathobiological role of gliotoxin in two different mouse strains, 129/Sv and BALB/c, that were immunosuppressed by hydrocortisone alone to avoid neutropenia. These strains of mice were infected using the isogenic set of a wild type (B-5233) and its mutant strain (gliPDelta), and the the glip reconstituted strain (gliPR). The gliP gene encodes a non-ribosomal peptide synthase that catalyzes the first step in gliotoxin biosynthes. The gliPDelta strain was significantly less virulent than B-5233 or gliPR in both mouse models. In vitro assays with culture filtrates (CFs) of B-5233, gliPDelta and gliPR strains showed the following: 1. Deletion of gliP abrogated gliotoxin production as determined by HPLC analysis; 2) Unlike the CFs from B-5233 and gliPR, gliPDelta CF failed to induce proapoptotic processes in EL4 thymoma cells, as tested by Bak conformational change, mitochondrial membrane potential disruption, superoxide production, caspase-3 activation and phosphatidylserine translocation. Furthermore, superoxide production in human neutrophils was strongly inhibited by CFs from B-5233 and gliPR, but not gliPDelta. Our study confirms that gliotoxin is an important virulence determinant of AF and that the type of the immunosuppression regimen used is important to reveal the pathogenic potential of gliotoxin.