fgene-11-00459 May 12, 2020 Time: 14:29 # 1

ORIGINAL RESEARCH published: 12 May 2020 doi: 10.3389/fgene.2020.00459

Genomic and Phenotypic Heterogeneity of Clinical Isolates of the Human Pathogens fumigatus, Aspergillus lentulus, and Aspergillus fumigatiaffinis

Renato A. C. dos Santos1,2, Jacob L. Steenwyk2, Olga Rivero-Menendez3, Matthew E. Mead2, Lilian P. Silva1, Rafael W. Bastos1, Ana Alastruey-Izquierdo3, Gustavo H. Goldman1* and Antonis Rokas2*

1 Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Edited by: Paulo, São Paulo, Brazil, 2 Department of Biological Sciences, Vanderbilt University, Nashville, TN, United States, 3 Medical Bridget Marie Barker, Mycology Reference Laboratory, National Center for Microbiology, Instituto de Salud Carlos III, Madrid, Spain Northern Arizona University, United States Reviewed by: Fungal pathogens are a global threat to human health. For example, fungi from the Megan C. McDonald, genus Aspergillus cause a spectrum of diseases collectively known as aspergillosis. Australian National University, Most of the 200,000 life-threatening aspergillosis infections per year worldwide are Australia > Praveen Rao Juvvadi, caused by . Recently, molecular typing techniques have revealed Duke University, United States that aspergillosis can also be caused by organisms that are phenotypically similar *Correspondence: to A. fumigatus but genetically distinct, such as Aspergillus lentulus and Aspergillus Gustavo H. Goldman [email protected] fumigatiaffinis. Importantly, some of these so-called cryptic are thought to Antonis Rokas exhibit different virulence and drug susceptibility profiles than A. fumigatus, however, [email protected] our understanding of their biology and pathogenic potential has been stymied by the

Specialty section: lack of genome sequences and phenotypic profiling of multiple clinical strains. To fill this This article was submitted to gap, we phenotypically characterized the virulence and drug susceptibility of 15 clinical Evolutionary and Genomic Microbiology, strains of A. fumigatus, A. lentulus, and A. fumigatiaffinis from Spain and sequenced their a section of the journal genomes. We found heterogeneity in drug susceptibility across species and strains. We Frontiers in Genetics further found heterogeneity in virulence within each species but no significant differences Received: 28 February 2020 in the virulence profiles between the three species. Genes known to influence drug Accepted: 14 April 2020 Published: 12 May 2020 susceptibility (cyp51A and fks1) vary in paralog number and sequence among these Citation: species and strains and correlate with differences in drug susceptibility. Similarly, genes dos Santos RAC, Steenwyk JL, known to be important for virulence in A. fumigatus showed variability in number of Rivero-Menendez O, Mead ME, Silva LP, Bastos RW, paralogs across strains and across species. Characterization of the genomic similarities Alastruey-Izquierdo A, Goldman GH and differences of clinical strains of A. lentulus, A. fumigatiaffinis, and A. fumigatus and Rokas A (2020) Genomic that vary in disease-relevant traits will advance our understanding of the variance in and Phenotypic Heterogeneity of Clinical Isolates of the Human pathogenicity between Aspergillus species and strains that are collectively responsible Pathogens Aspergillus fumigatus, for the vast majority of aspergillosis infections in humans. Aspergillus lentulus, and Aspergillus fumigatiaffinis. Front. Genet. 11:459. Keywords: Aspergillus, antifungal drug susceptibility, genomics, strain heterogeneity, drug resistance, cryptic doi: 10.3389/fgene.2020.00459 species, virulence, genetic determinants of virulence

Frontiers in Genetics| www.frontiersin.org 1 May 2020| Volume 11| Article 459 fgene-11-0