Aspergillus section Fumigati molds: A model lineage for studying the repeated evolution of fungal pathogenicity

Author:

ME Mead1, JL Steenwyk1, HA Raja2, SL Knowles2, LP Silva3, GH Goldman3,
NH Oberlies2, A Rokas1

Author address:

1Biological Sciences, Vanderbilt University, Nashville, USA
2Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, USA
3Faculdade de Ciencias Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

Full conference title:

9th Advances Against Aspergillosis

Date: 26 February 2020

Abstract:

Purpose: Approximately 70% of all Aspergillus infections are caused by A. fumigatus, whereas the remaining 30% stem from other species in the genus. Some of these other pathogens are closely related to A. fumigatus and also belong in the taxonomic section Fumigati. However, the majority of species in section Fumigati are not pathogenic, and we know surprisingly little about the evolution of pathogenicity in section Fumigati.

Methods: To study the evolution of pathogenicity in section Fumigati, we have taken a multi-pronged approach that utilizes comparative genomics, in vitro phenotyping, chemistry, and multiple disease models of aspergillosis.

Results: Our examination of the distribution of pathogenic species in our newly-constructed, genome-scale phylogeny of section Fumigati revealed that A. fumigatus pathogenicity likely evolved after the species diverged from A. oerlinghausenensis and A. fischeri, the two non-pathogenic species that are most closely related to A. fumigatus. Interestingly, we found that this was also the case for other pathogenic species (ex. A. udagawae and A. thermomutatus), suggesting that pathogenicity independently arose multiple times in section Fumigati.

To further investigate one of these pathogenicity events, we compared A. fischeri and A. fumigatus for traits important for human disease. We discovered that A. fischeri was less virulent than A. fumigatus in a mouse model of disease, less tolerant than A. fumigatus to human body temperature and oxidative stress, and produced both unique and shared secondary metabolites. Genomic analyses of A. fischeri, A. fumigatus, and other section Fumigati species showed that most of the A. fumigatus genes known to be associated with virulence are highly conserved, including in non-pathogens like A. fischeri.

To determine if a genetic determinant of virulence in A. fumigatus that is conserved throughout section Fumigati functions similarly in A. fischeri, we deleted laeA, a master regulator of secondary metabolism. The wild type strain of A. fischeri was less pathogenic than A. fumigatus in a Galleria mellonella larval model of disease, but the pathogenicity of the DlaeA A. fischeri strain was indistinguishable from wild type A. fischeri. This is a striking finding considering the conserved role we discovered laeA plays in the regulation of secondary metabolism in A. fischeri and the published evidence connecting secondary metabolism and laeA to pathogenicity in A. fumigatus.

Finally, we examined the evolutionary rates of genes like laeA that are found both in pathogenic and non-pathogenic species. We discovered that genes in highly pathogenic species exhibited higher rates of evolution than their homologs in species with medium levels of pathogenicity, which in turn evolved faster than their copies in lowly (or non-) pathogenic species. We hypothesize that the faster evolutionary rates in pathogenic species have facilitated their ability to adapt to the challenging environment of the human host.

Conclusion: Our results show that pathogenicity in section Fumigati has independently evolved multiple times, reveal that traits (but few genes) associated with virulence in A. fumigatus differ across species in section Fumigati, and establish a broad framework for studying how major fungal pathogens evolve from historically innocuous organisms.

Abstract Number: 51

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Link Conference abstract: 

AAAM 2020

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