Gliotoxin, a Known Virulence Factor in the Major Human Pathogen Aspergillus fumigatus, Is Also Biosynthesized by Its Nonpathogenic Relative Aspergillus fischeri

Autor(es)

Knowles, Sonja L. ^[1] ; Mead, Matthew E. ^[2] ; Silva, Lilian Pereira ^[3] ; Raja, Huzefa A. ^[1] ; Steenwyk, Jacob L. ^[2] ; Goldman, Gustavo H. ^[3] ; Oberlies, Nicholas H. ^[1] ; Rokas, Antonis ^[2]

Afiliação do(s) autor(es)

^[1] Univ North Carolina Greensboro, Dept Chem & Biochem, Greensboro, NC 27412 - USA

^[2] Vanderbilt Univ, Dept Biol Sci, 221 Kirkland Hall, Nashville, TN 37235 - USA

^[3] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: MBIO; v. 11, n. 1 JAN-FEB 2020.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 16/21392-2 - "Caracterização dos fatores de transcrição que têm o domínio básico de "zipper" de leucina (bZIP) ATF1 em Aspergillus fumigatus"
• Beneficiário: Lilian Pereira Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/07870-9 - A influência de proteínas quinases ativadas por mitógenos (MAPK) na expressão de determinantes genéticos importantes para a virulência de Aspergillus fumigatus
• Beneficiário: Gustavo Henrique Goldman
• Modalidade de apoio: Auxílio à Pesquisa - Temático