Gliotoxin in Aspergillus fumigatus: an example that mycotoxins are potential virulence factors

Hof, Herbert; Kupfahl, Claudio

doi:10.1007/s12550-009-0020-4

Cited by 29 publications

(22 citation statements)

References 66 publications

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“…Gliotoxin is a small, hydrophobic nonribosomal dipeptide that exerts toxic effects on phagocytic cells and T‐lymphocytes at low concentrations in vitro . It is discussed as a virulence factor in invasive aspergillosis by suppressing the innate and adaptive immune response 34.…”

Section: Resultsmentioning

confidence: 99%

Functional genomic profiling of Aspergillus fumigatus biofilm reveals enhanced production of the mycotoxin gliotoxin

et al. 2010

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The opportunistic pathogenic mold Aspergillus fumigatus is an increasing cause of morbidity and mortality in immunocompromised and in part immunocompetent patients. A. fumigatus can grow in multicellular communities by the formation of a hyphal network encased in an extracellular matrix. Here, we describe the proteome and transcriptome of planktonic- and biofilm-grown A. fumigatus mycelium after 24 and 48 h. A biofilm- and time-dependent regulation of many proteins and genes of the primary metabolism indicates a developmental stage of the young biofilm at 24 h, which demands energy. At a matured biofilm phase, metabolic activity seems to be reduced. However, genes, which code for hydrophobins, and proteins involved in the biosynthesis of secondary metabolites were significantly upregulated. In particular, proteins of the gliotoxin secondary metabolite gene cluster were induced in biofilm cultures. This was confirmed by real-time PCR and by detection of this immunologically active mycotoxin in culture supernatants using HPLC analysis. The enhanced production of gliotoxin by in vitro formed biofilms reported here may also play a significant role under in vivo conditions. It may confer A. fumigatus protection from the host immune system and also enable its survival and persistence in chronic lung infections such as aspergilloma.

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Section: Resultsmentioning

confidence: 99%

Functional genomic profiling of Aspergillus fumigatus biofilm reveals enhanced production of the mycotoxin gliotoxin

et al. 2010

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“…ellipticus producing gliotoxin and in much higher amounts. This finding, as well as the role that gliotoxin likely plays in virulence enhancement (Kupfahl et al ., ; Hof & Kupfahl, ; Kwon‐Chung & Sugui, ), makes it very interesting to evaluate the possible virulence characteristics of the variant ellipticus in future research. In addition, more research is needed to evaluate the importance of this variant in invasive infections.…”

Section: Discussionmentioning

confidence: 99%

“…gliotoxin). Increasing evidence supports a significant role of gliotoxin in hampering various defence mechanisms of the host, leading to virulence enhancement (Kupfahl et al ., ; Hof & Kupfahl, ; Kwon‐Chung & Sugui, ). The level of gliotoxin production by A. fumigatus isolates can vary or even be completely absent (Lewis et al ., ; Kosalec & Pepeljnjak, ; Boudra & Morgavi, ; Kupfahl et al ., ; Pereyra et al ., ; E. Van Pamel, E. Daeseleire, M. Heyndrickx, L. Herman, A. Verbeken & G. Vlaemynck, unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Restriction analysis of an amplified rodA gene fragment to distinguish Aspergillus fumigatus var. ellipticus from Aspergillus fumigatus var. fumigatus

Pamel¹,

Daeseleire²,

Clercq³

et al. 2012

FEMS Microbiol Lett

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A previous multidisciplinary study indicated that gliotoxin-producing Aspergillus fumigatus Fresen. isolates from silage commodities mostly belonged to its variant A. fumigatus var. ellipticus Raper & Fennell. Sequence analysis revealed the presence of a single nucleotide polymorphism at five positions in a fragment of the rodA gene (coding for a hydrophobin rodletA protein) between Aspergillus fumigatus var. fumigatus and Aspergillus fumigatus var. ellipticus. A method was developed to distinguish these two types of isolates based on restriction analysis of this rodA gene fragment using the HinfI restriction enzyme. In addition, in silico analysis of 113 rodA gene fragments retrieved from GenBank was performed and confirmed the suitability of this method. In conclusion, the method developed in this study allows easy distinction between A. fumigatus var. fumigatus and its variant ellipticus. In combination with the earlier developed PCR-restriction fragment length polymorphism method of Staab et al. (2009, J Clin Microbiol 47: 2079), this method is part of a sequencing-independent identification scheme that allows for rapid distinction between similar species/variants within Aspergillus section Fumigati, specifically A. fumigatus, A. fumigatus var. ellipticus, Aspergillus lentulus Balajee & K.A. Marr, Neosartorya pseudofischeri S.W. Peterson and Neosartorya udagawae Y. Horie, Miyaji & Nishim.

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“…Its most prominent member is the lipid-soluble gliotoxin which was shown to induce apoptosis, inhibit angiogenesis and prevent NF-κB activation by inhibiting the proteasome among other bioactivities ( Kroll et al, 1999 ; Pardo et al, 2006 ; Ben-Ami et al, 2009 ). High levels of gliotoxin are produced by Aspergillus fumigatus and it has been suggested that gliotoxin might be a virulence factor associated with invasive aspergillosis ( Hof and Kupfahl, 2009 ). A number of highly unusual transformations take place during gliotoxin biosynthesis including a stereospecific glutathione (GSH)- and pyridoxal phosphate (PLP)-dependent sulfurization of both C α atoms in the DKP-scaffold catalyzed by the sequential action of the glutathione S -transferase GliG, the peptidase GliJ and the thioesterase GliI [ Figure 1 , reaction (3)] ( Davis et al, 2011 ).…”

Section: Dkp Modification Enzymesmentioning

confidence: 99%

Rational and combinatorial tailoring of bioactive cyclic dipeptides

Giessen

Marahiel

2015

Front. Microbiol.

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Modified cyclic dipeptides represent a diverse family of microbial secondary metabolites. They display a broad variety of biological and pharmacological activities and have long been recognized as privileged structures with the ability to bind to a wide range of receptors. This is due to their conformationally constrained 2, 5-diketopiperazine (DKP) scaffold and the diverse set of DKP tailoring enzymes present in nature. After initial DKP assembly through different biosynthetic systems modifying enzymes are responsible for installing functional groups crucial for the biological activities of the resulting modified DKPs. They represent a vast and largely untapped enzyme repository very useful for synthetic biology approaches aiming at introducing structural variations into DKP scaffolds. In this review we focus on these DKP modification enzymes found in various microbial secondary metabolite gene clusters. We will give a brief overview of their distribution and highlight a select number of characterized DKP tailoring enzymes before turning to their application potential in combinatorial biosynthesis with the aim of producing molecules with improved or entirely new biological and medicinally relevant properties.

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Gliotoxin in Aspergillus fumigatus: an example that mycotoxins are potential virulence factors

Cited by 29 publications

References 66 publications

Functional genomic profiling of Aspergillus fumigatus biofilm reveals enhanced production of the mycotoxin gliotoxin

Functional genomic profiling of Aspergillus fumigatus biofilm reveals enhanced production of the mycotoxin gliotoxin

Restriction analysis of an amplified rodA gene fragment to distinguish Aspergillus fumigatus var. ellipticus from Aspergillus fumigatus var. fumigatus

Rational and combinatorial tailoring of bioactive cyclic dipeptides

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