Abstract
Gliotoxin (GT) is a fungal secondary metabolite that has attracted great interest due to its high biological activity since it was discovered by the 1930s. An inactive derivative of this molecule, bis(methylthio)gliotoxin (bmGT), has been proposed as an invasive aspergillosis (IA) biomarker. Nevertheless, studies regarding bmGT production among common opportunistic fungi, including the Aspergillus genus, are scarce and sometimes discordant. As previously reported, bmGT is produced from GT by a methyl-transferase, named as GtmA, as a negative feedback regulatory system of GT production. In order to analyze the potential of bmGT detection to enable identification of infections caused by different members of the Aspergillus genus we have assessed bmGT production within the genus Aspergillus, including A, fumigatus, A. niger, A. nidulans, and A. flavus, and its correlation with gtmA presence. In order to validate the relevance of our in vitro findings, we compared bmGT during in vitro culture with the presence of bmGT in sera of patients from whom the Aspergillus spp. were isolated. Our results indicate that most A. fumigatus isolates produce GT and bmGT both in vitro and in vivo. In contrast, A. niger and A. nidulans were not able to produce GT or bmGT, although A. niger produced bmGT from a exogenous GT source. The frequency and amount of bmGT production in A. terreus and A. flavus isolates in vitro was lower than in A. fumigatus. Our results suggest that this defect could be related to the in vitro culture conditions, since isolates that did not produce bmGT in vitro were able to synthetize it in vivo. In summary, our study indicates that bmGT could be very useful to specifically detect the presence of A. fumigatus, the most prevalent agent causing IA. Concerning A. terreus and A. flavus a higher number of analyses from sera from infected patients will be required to reach a useful conclusion.
Highlights
More than 20 years ago the first invasive aspergillosis (IA) biomarker, galactomannan (GM), was developed based on an enzyme linked immunosorbent assay (Stynen et al, 1995)
The production of GT and bmGT was tested in culture supernatants of 252 Aspergillus isolates from the species complexes A. fumigatus, A. flavus, A. terreus, A. niger, and A. nidulans after 4 days of incubation
All cultures were analyzed by High Performance Thin Layer Chromatography (HPTLC), a method to detect GT and bmGT previously optimized and validated versus LC-MS (Domingo et al, 2012), and some of the results in selected culture isolates of A. fumigatus, A. niger, A. nidulans, and A. flavus, were confirmed by LC-MS
Summary
More than 20 years ago the first invasive aspergillosis (IA) biomarker, galactomannan (GM), was developed based on an enzyme linked immunosorbent assay (Stynen et al, 1995) It stirred up the diagnosis of this lethal infectious disease, as it allowed to detect the infection when combined with clinical signs and symptoms (Maertens et al, 1999, 2002). New diagnostic approaches were developed based on the increased accuracy of these tests, such as pre-emptive therapy (Wingard, 2007; Riwes and Wingard, 2012) Despite of these advances, IA management continues to be challenging due to the heterogeneous population at risk, the diversity of clinical and radiological presentations and the lack of a gold standard (Lamoth and Calandra, 2017). The future directions in IA diagnosis research need to focus on the development of new biomarkers, including a clear understanding of their strengths and limitations, along with the assessment of their utility in well-designed clinical trials (Arvanitis and Mylonakis, 2015; Mercier and Maertens, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
