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Characterizing the pathogenic, genomic, and chemical traits of Aspergillus fischeri, a close relative of the major human fungal pathogen Aspergillus fumigatus

Matthew E. Mead, Sonja L. Knowles, Huzefa A. Raja, Sarah R. Beattie, Caitlin H. Kowalski, Jacob L. Steenwyk, Lilian P. Silva, Jessica Chiaratto, Laure N.A. Ries, Gustavo H. Goldman, Robert A. Cramer, Nicholas H. Oberlies, View ORCID ProfileAntonis Rokas
doi: https://doi.org/10.1101/430728
Matthew E. Mead
aDepartment of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA
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Sonja L. Knowles
bDepartment of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA
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Huzefa A. Raja
bDepartment of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA
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Sarah R. Beattie
cDepartment of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
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Caitlin H. Kowalski
cDepartment of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
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Jacob L. Steenwyk
aDepartment of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA
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Lilian P. Silva
dFaculdade de Ciencias Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil
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Jessica Chiaratto
dFaculdade de Ciencias Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil
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Laure N.A. Ries
dFaculdade de Ciencias Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil
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Gustavo H. Goldman
dFaculdade de Ciencias Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil
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Robert A. Cramer
cDepartment of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
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Nicholas H. Oberlies
bDepartment of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA
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Antonis Rokas
aDepartment of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA
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  • ORCID record for Antonis Rokas
  • For correspondence: Antonis.rokas@vanderbilt.edu
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Abstract

Aspergillus fischeri is closely related to Aspergillus fumigatus, the major cause of invasive mold infections. Even though A. fischeri is commonly found in diverse environments, including hospitals, it rarely causes invasive disease; why that is so is unclear. Comparison of A. fischeri and A. fumigatus for diverse pathogenic, genomic, and secondary metabolic traits revealed multiple differences for pathogenesis-related phenotypes, including that A. fischeri is less virulent than A. fumigatus in multiple animal models of disease, grows slower in low oxygen environments, and is more sensitive to oxidative stress. In contrast, the two species exhibit high genomic similarity; ~90% of the A. fumigatus proteome is conserved in A. fischeri, including 48/49 genes known to be involved in A. fumigatus virulence. However, only 10/33 A. fumigatus biosynthetic gene clusters (BGCs) likely involved in secondary metabolite production are conserved in A. fischeri and only 13/48 A. fischeri BGCs are conserved in A. fumigatus. Detailed chemical characterization of A. fischeri cultures grown on multiple substrates identified multiple secondary metabolites, including two new compounds and one never before isolated as a natural product. Interestingly, an A. fischeri deletion mutant of laeA, a master regulator of secondary metabolism, produced fewer secondary metabolites and in lower quantities, suggesting that regulation of secondary metabolism is at least partially conserved. These results suggest that the non-pathogenic A. fischeri possesses many of the genes important for A. fumigatus pathogenicity but is divergent with respect to its ability to thrive under host-relevant conditions and its secondary metabolism.

Importance Aspergillus fumigatus is the primary cause of aspergillosis, a devastating ensemble of diseases associated with severe morbidity and mortality worldwide. A. fischeri is a close relative of A. fumigatus, but is not generally observed to cause human disease. To gain insights into the underlying causes of this remarkable difference in pathogenicity, we compared two representative strains (one from each species) for a range of host-relevant biological and chemical characteristics. We found that disease progression in multiple A. fischeri mouse models was slower and caused less mortality than A. fumigatus. The two species also exhibited different growth profiles when placed in a range of stress-inducing conditions encountered during infection, such as low levels of oxygen and the presence of reactive oxygen species-inducing agents. Interestingly, we also found that the vast majority of A. fumigatus genes known to be involved in virulence are conserved in A. fischeri, whereas the two species differ significantly in their secondary metabolic pathways. These similarities and differences that we identified are the first step toward understanding the evolutionary origin of a major fungal pathogen.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 07, 2018.
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Characterizing the pathogenic, genomic, and chemical traits of Aspergillus fischeri, a close relative of the major human fungal pathogen Aspergillus fumigatus
Matthew E. Mead, Sonja L. Knowles, Huzefa A. Raja, Sarah R. Beattie, Caitlin H. Kowalski, Jacob L. Steenwyk, Lilian P. Silva, Jessica Chiaratto, Laure N.A. Ries, Gustavo H. Goldman, Robert A. Cramer, Nicholas H. Oberlies, Antonis Rokas
bioRxiv 430728; doi: https://doi.org/10.1101/430728
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Characterizing the pathogenic, genomic, and chemical traits of Aspergillus fischeri, a close relative of the major human fungal pathogen Aspergillus fumigatus
Matthew E. Mead, Sonja L. Knowles, Huzefa A. Raja, Sarah R. Beattie, Caitlin H. Kowalski, Jacob L. Steenwyk, Lilian P. Silva, Jessica Chiaratto, Laure N.A. Ries, Gustavo H. Goldman, Robert A. Cramer, Nicholas H. Oberlies, Antonis Rokas
bioRxiv 430728; doi: https://doi.org/10.1101/430728

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