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Fungal toxins are considered secondary metabolites which may provide selective advantage under particular conditons. 

In this section, we discuss the epipolythiodioxopiperazines (ETPs) with special reference to Gliotoxin. The class of ETP fungal toxins has been reviewed and you are referred to this review for further detail (Gardiner et al, 2005). 

The ETPs are produced by a wide variety of fungi, e.g., Aspergillus spp, Chaetomium spp, Penicillium spp, to mention a few. However, Gliotoxin produced by Aspergillus fumigatus has received wide attention because it is considered a virulence factor for A. fumigatus, as well as being present in the sera of cancer patients with aspergillosis (Sugui et al, 2007; Sugui et al, 2007; Bok et al, 2006). 

Gliotoxin has been detected in the lung tissue and sera of mice with invasive aspergillosis and sera of cancer patients (Lewis et al, 2005a). The percentage of Aspergillus isolates from cancer patients produced gliotoxin as follows: fumigatus (93 %), niger (75 %), terreus (25 %) and flavus (4 %). (Lewis et al, 2005b). However, only 18 % of A. fumigatus in European patients produce gliotoxin, while 23 % of A. flavus isolates produced aflatoxin B1 (Kosalec and Pepeljnjak, 2005). The difference between the two reports may result from differences in strains of A. fumigatus in culture media and temperature (Kosalec et al, 2005).

The pathobiology of gliotoxin is multi-faceted (Kwon-Chung and Sugui, 2009). These are: 1) the S-S group in the ring forms adducts with cysteine residues of proteins; 2) The S-S group readily goes through a redox cycle production reactive oxygen species (ROS); 3) gliotoxin is immunosuppressive inhibiting phagocytosis; blocking NF-kB transcription factor, inhibiting proinflammatory response and cytokine production; 4) causes mitochondrial directed apoptosis ; 5) induces PM-mediated inflammation in organ transplant patients treated with corticosteroids.; and 6) the mycotoxin probably inhibits normal neutrophil functions in healthy subjects.

Finally, it was believed that gliotoxin was produced by the yeast Candida albicans. However, this observation has recently been questioned (Kupfahl et al 2007).

In conclusion, several species of Aspergillus and other fungi, as well as possibly yeast, produced gliotoxin both in vitro and in vivo. More attention should be paid to this mycotoxin because of its multi--faceted toxic properties.
Aspergillosis in a fungal ball

Gliotoxin has been found in aspergillosis
(slide of aspergillosis fungal ball)


Epidithiodioxopiperazines (ETPs)


Bok JW, Chung D, Alajee SA, Marr KA, Andes D, et al, 2006. GliZ, a transcriptional regulator of gliotoxin biosynthesis contributes to Aspergillus fumigatus virulence. Infect Immun 74:6761-8.

Gardiner DM, Waring P, Howlett BJ. 2005. The epipolythiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis. Microbiol 151:1021-32.

Kosalec I, Pepeljnjak S. 2005. Mycotoxigenicity of clinical and environmental Aspergillus fumigatus and A. flavus isolates. Acta Pharm 55:365-75.

Kosalec I, Pepeljnjak S, Jandric M. 2005 Influence of media and temperature on gliotoxin production in Aspergillus fumigatus strains. Arh Hig Rada Toksikol 56:269-73.

Kuwon-Chung KJ, Sugui JA. 2009. What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus? Med Mycol 47(Suppl 1):S97-103.

Kupfahl C, Ruppert T, Dietz A, Gerinat G, Hof H. 2007. Candida species fail to produce the immunosuppressive secondary metabolite gliotoxin in vitro. FEMS Yeast Res 7:986-92.

Lewis RE, Wiederhold NP, Chi J, Han XY, Komanduri K, et al. 2005a. Detection of gliotoxin in experimental and human aspergillosis. Infect Immun 73:635-7.

Lewis RE, Wiederhold NP, Lionakis S, Prince RA, Kontoyiannis DP. 2005b. Frequency and species of gliotoxins-producing Aspergillus isolates from patients at a tertiary-care cancer center. J Clin Microbiol 43:6120-2.

Sugui JA, Pardo J, Chang YC, Zarember KA. 2007a. Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunocompromised with hydrocortisone. Eukaryotic Cell 6:2562-9.

Sugui JA, Pardo J, Chang YC, Mullbacher A, et al 2007b. Role of LaeA in the regulation fo alb1, bliP, conidial morphology, and virulence of Aspergillus fumigatus. Eukaryotic Cell. 6:1552-61.

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