Immunosuppression in vitro by a metabolite of a human pathogenic fungus.

Abstract

Gliotoxin, a metabolite of Aspergillus fumigatus, inhibits phagocytosis of macrophages at concentrations of 20-50 ng/ml. Pretreatment of stimulator cells in mixed lymphocyte cultures with gliotoxin (1QQ ng/ml) abrogates induction of alloreactive cytotoxic T cells. The presence of gliotoxin 48 hr after initiation of cytotoxic T-cell induction has no effect. Inhibition of cytotoxic T-cell induction by gliotoxin at low concentrations, acting on the stimulator cells, can be overridden by concanavajin A-activated cell supernatants. Gliotoxin does not induce immediate cell-surfpce antigen modification on target cells. The possible role of gliotoxin in the etiology of A. fumigatus-related diseases is discussed.Fungal metabolites have been extensively investigated for their antimicrobial activities since the fortuitous discovery of penicillin by Fleming. Little is known, however, apart from general toxicological studies on eukaryotic cells, about their effect on specific tissue such as the hemopoietic system. One fungal metabolite, cyclosporin A, has recently gained worldwide attention as a potent immunosuppressive agent. Cyclosporin A has been investigated as an immunoregulatory agent in clinical practice, such as organ transplantation, as well as a tool in fundamental immunological research (1). It appears to act on the T lymphocyte, especially the T helper subset responsible for release of interleukin 2 after antigen recognition (1). Problems associated with cyclosporin A are nephrotoxicity, relatively high concentrations required for activity, and its low solubility in aqueous solutions.Aspergillus fumigatus, a member of the order Eurotiales, has been shown to be associated with a number of lung diseases in vertebrates including man (2-4). A. fumigatus produces a variety of toxic substances including gliotoxin, a compound containing an epidithiadioxopiperazine ring, which possesses antimicrobial activity in vitro (5). However, little is known regarding the effect of any of these fungal metabolites in vivo and their possible role in the etiology of A. fumigatus-related diseases.We now report on the immunosuppressive and anti-phagocytic activity of gliotoxin in vitro and its possible role in the pathogenesis of A. fumigatus-induced diseases.

Exacerbation of invasive aspergillosis by the immunosuppressive fungal metabolite, gliotoxin

“…'° Tang et al achieved growth of . 4. fumigatus in the lungs via intranasal infection but did not report any invasive disease occutTing in other internal organs.-" This difference, however, is unlikely to be of consequence in extrapolation of the observations made in our experimental mouse model to the human disease.…”

Dendritic cell-mediated stimulation of the in vitro lymphocyte response to Aspergillus

“…18,19 DC have been observed to phagocytose whole bacteria, but whether large particles, such as whole fungal conidia, could be taken up was unknown. Moreover, toxic metabolites of A. fumigatus are known to inhibit phagocytosis, 20 raising further doubts about the phagocytic capacity of DC for this fungus. However, we have shown here that DC generated ex vivo take up A. fumigatus conidia without apparent adverse effects to the cells.…”

Translocation of proteins homologous to human neutrophil p47phox and p67phox to the cell membrane in activated hemocytes of Galleria mellonella

“…Gliotoxin (GT), one of the major metabolites produced by A. fumigatus and an inhibitor employed in this study, has received particular attention because it has potent immunosuppressive [35], genotoxic, cytotoxic [36] and apoptotic effects [37]. In addition this toxin has been associated with cases of clinical aspergillosis [38,39].…”