Gliotoxin, a Known Virulence Factor in the Major Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>, Is Also Biosynthesized by Its Nonpathogenic Relative <italic toggle="yes">Aspergillus fischeri</italic>

ABSTRACT Aspergillus fumigatus is a major opportunistic human pathogen. Multiple traits contribute to A. fumigatus pathogenicity, including its ability to produce specific secondary metabolites, such as gliotoxin. Gliotoxin is known to inhibit the host immune response, and genetic mutants that inact...

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Autores principales:	Sonja L. Knowles, Matthew E. Mead, Lilian Pereira Silva, Huzefa A. Raja, Jacob L. Steenwyk, Gustavo H. Goldman, Nicholas H. Oberlies, Antonis Rokas
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	fungal pathogenesis secondary metabolism gliotoxin specialized metabolism evolution of virulence laeA Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/640b52c900b54ab28608595e634c7262
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spelling	oai:doaj.org-article:640b52c900b54ab28608595e634c72622021-11-15T15:56:58ZGliotoxin, a Known Virulence Factor in the Major Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>, Is Also Biosynthesized by Its Nonpathogenic Relative <italic toggle="yes">Aspergillus fischeri</italic>10.1128/mBio.03361-192150-7511https://doaj.org/article/640b52c900b54ab28608595e634c72622020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03361-19https://doaj.org/toc/2150-7511ABSTRACT Aspergillus fumigatus is a major opportunistic human pathogen. Multiple traits contribute to A. fumigatus pathogenicity, including its ability to produce specific secondary metabolites, such as gliotoxin. Gliotoxin is known to inhibit the host immune response, and genetic mutants that inactivate gliotoxin biosynthesis (or secondary metabolism in general) attenuate A. fumigatus virulence. The genome of Aspergillus fischeri, a very close nonpathogenic relative of A. fumigatus, contains a biosynthetic gene cluster that is homologous to the A. fumigatus gliotoxin cluster. However, A. fischeri is not known to produce gliotoxin. To gain further insight into the similarities and differences between the major pathogen A. fumigatus and the nonpathogen A. fischeri, we examined whether A. fischeri strain NRRL 181 biosynthesizes gliotoxin and whether the production of secondary metabolites influences the virulence profile of A. fischeri. We found that A. fischeri biosynthesizes gliotoxin under the same conditions as A. fumigatus. However, whereas loss of laeA, a master regulator of secondary metabolite production (including gliotoxin biosynthesis), has previously been shown to reduce A. fumigatus virulence, we found that laeA loss (and loss of secondary metabolite production) in A. fischeri does not influence its virulence. These results suggest that LaeA-regulated secondary metabolites are virulence factors in the genomic and phenotypic background of the major pathogen A. fumigatus but are much less important in the background of the nonpathogen A. fischeri. Understanding the observed spectrum of pathogenicity across closely related pathogenic and nonpathogenic Aspergillus species will require detailed characterization of their biological, chemical, and genomic similarities and differences. IMPORTANCE Aspergillus fumigatus is a major opportunistic fungal pathogen of humans, but most of its close relatives are nonpathogenic. Why is that so? This important, yet largely unanswered, question can be addressed by examining how A. fumigatus and its close nonpathogenic relatives are similar or different with respect to virulence-associated traits. We investigated whether Aspergillus fischeri, a nonpathogenic close relative of A. fumigatus, can produce gliotoxin, a mycotoxin known to contribute to A. fumigatus virulence. We discovered that the nonpathogenic A. fischeri produces gliotoxin under the same conditions as those of the major pathogen A. fumigatus. However, we also discovered that, in contrast to what has previously been observed in A. fumigatus, the loss of secondary metabolite production in A. fischeri does not alter its virulence. Our results are consistent with the “cards of virulence” model of opportunistic fungal disease, in which the ability to cause disease stems from the combination (“hand”) of virulence factors (“cards”) but not from individual factors per se.Sonja L. KnowlesMatthew E. MeadLilian Pereira SilvaHuzefa A. RajaJacob L. SteenwykGustavo H. GoldmanNicholas H. OberliesAntonis RokasAmerican Society for Microbiologyarticlefungal pathogenesissecondary metabolismgliotoxinspecialized metabolismevolution of virulencelaeAMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	fungal pathogenesis secondary metabolism gliotoxin specialized metabolism evolution of virulence laeA Microbiology QR1-502
spellingShingle	fungal pathogenesis secondary metabolism gliotoxin specialized metabolism evolution of virulence laeA Microbiology QR1-502 Sonja L. Knowles Matthew E. Mead Lilian Pereira Silva Huzefa A. Raja Jacob L. Steenwyk Gustavo H. Goldman Nicholas H. Oberlies Antonis Rokas Gliotoxin, a Known Virulence Factor in the Major Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>, Is Also Biosynthesized by Its Nonpathogenic Relative <italic toggle="yes">Aspergillus fischeri</italic>
description	ABSTRACT Aspergillus fumigatus is a major opportunistic human pathogen. Multiple traits contribute to A. fumigatus pathogenicity, including its ability to produce specific secondary metabolites, such as gliotoxin. Gliotoxin is known to inhibit the host immune response, and genetic mutants that inactivate gliotoxin biosynthesis (or secondary metabolism in general) attenuate A. fumigatus virulence. The genome of Aspergillus fischeri, a very close nonpathogenic relative of A. fumigatus, contains a biosynthetic gene cluster that is homologous to the A. fumigatus gliotoxin cluster. However, A. fischeri is not known to produce gliotoxin. To gain further insight into the similarities and differences between the major pathogen A. fumigatus and the nonpathogen A. fischeri, we examined whether A. fischeri strain NRRL 181 biosynthesizes gliotoxin and whether the production of secondary metabolites influences the virulence profile of A. fischeri. We found that A. fischeri biosynthesizes gliotoxin under the same conditions as A. fumigatus. However, whereas loss of laeA, a master regulator of secondary metabolite production (including gliotoxin biosynthesis), has previously been shown to reduce A. fumigatus virulence, we found that laeA loss (and loss of secondary metabolite production) in A. fischeri does not influence its virulence. These results suggest that LaeA-regulated secondary metabolites are virulence factors in the genomic and phenotypic background of the major pathogen A. fumigatus but are much less important in the background of the nonpathogen A. fischeri. Understanding the observed spectrum of pathogenicity across closely related pathogenic and nonpathogenic Aspergillus species will require detailed characterization of their biological, chemical, and genomic similarities and differences. IMPORTANCE Aspergillus fumigatus is a major opportunistic fungal pathogen of humans, but most of its close relatives are nonpathogenic. Why is that so? This important, yet largely unanswered, question can be addressed by examining how A. fumigatus and its close nonpathogenic relatives are similar or different with respect to virulence-associated traits. We investigated whether Aspergillus fischeri, a nonpathogenic close relative of A. fumigatus, can produce gliotoxin, a mycotoxin known to contribute to A. fumigatus virulence. We discovered that the nonpathogenic A. fischeri produces gliotoxin under the same conditions as those of the major pathogen A. fumigatus. However, we also discovered that, in contrast to what has previously been observed in A. fumigatus, the loss of secondary metabolite production in A. fischeri does not alter its virulence. Our results are consistent with the “cards of virulence” model of opportunistic fungal disease, in which the ability to cause disease stems from the combination (“hand”) of virulence factors (“cards”) but not from individual factors per se.
format	article
author	Sonja L. Knowles Matthew E. Mead Lilian Pereira Silva Huzefa A. Raja Jacob L. Steenwyk Gustavo H. Goldman Nicholas H. Oberlies Antonis Rokas
author_facet	Sonja L. Knowles Matthew E. Mead Lilian Pereira Silva Huzefa A. Raja Jacob L. Steenwyk Gustavo H. Goldman Nicholas H. Oberlies Antonis Rokas
author_sort	Sonja L. Knowles
title	Gliotoxin, a Known Virulence Factor in the Major Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>, Is Also Biosynthesized by Its Nonpathogenic Relative <italic toggle="yes">Aspergillus fischeri</italic>
title_short	Gliotoxin, a Known Virulence Factor in the Major Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>, Is Also Biosynthesized by Its Nonpathogenic Relative <italic toggle="yes">Aspergillus fischeri</italic>
title_full	Gliotoxin, a Known Virulence Factor in the Major Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>, Is Also Biosynthesized by Its Nonpathogenic Relative <italic toggle="yes">Aspergillus fischeri</italic>
title_fullStr	Gliotoxin, a Known Virulence Factor in the Major Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>, Is Also Biosynthesized by Its Nonpathogenic Relative <italic toggle="yes">Aspergillus fischeri</italic>
title_full_unstemmed	Gliotoxin, a Known Virulence Factor in the Major Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>, Is Also Biosynthesized by Its Nonpathogenic Relative <italic toggle="yes">Aspergillus fischeri</italic>
title_sort	gliotoxin, a known virulence factor in the major human pathogen <named-content content-type="genus-species">aspergillus fumigatus</named-content>, is also biosynthesized by its nonpathogenic relative <italic toggle="yes">aspergillus fischeri</italic>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/640b52c900b54ab28608595e634c7262
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Gliotoxin, a Known Virulence Factor in the Major Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>, Is Also Biosynthesized by Its Nonpathogenic Relative <italic toggle="yes">Aspergillus fischeri</italic>

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