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The Influence of Genetic Stability on Aspergillus fumigatus Virulence and Azole Resistance

Genetic stability is extremely important for the survival of every living organism, and a very complex set of genes has evolved to cope with DNA repair upon DNA damage. Here, we investigated the Aspergillus fumigatus AtmA (Ataxia-telangiectasia mutated, ATM) and AtrA kinases, and how they impact vir...

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Detalles Bibliográficos
Autores principales: dos Reis, Thaila Fernanda, Silva, Lilian Pereira, de Castro, Patrícia Alves, Almeida de Lima, Pollyne Borborema, do Carmo, Rafaela Andrade, Marini, Marjorie Mendes, da Silveira, José Franco, Ferreira, Beatriz Henriques, Rodrigues, Fernando, Malavazi, Iran, Goldman, Gustavo H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Genetics Society of America 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765354/
https://www.ncbi.nlm.nih.gov/pubmed/29150592
http://dx.doi.org/10.1534/g3.117.300265
Descripción
Sumario:Genetic stability is extremely important for the survival of every living organism, and a very complex set of genes has evolved to cope with DNA repair upon DNA damage. Here, we investigated the Aspergillus fumigatus AtmA (Ataxia-telangiectasia mutated, ATM) and AtrA kinases, and how they impact virulence and the evolution of azole resistance. We demonstrated that A. fumigatus atmA and atrA null mutants are haploid and have a discrete chromosomal polymorphism. The ΔatmA and ΔatrA strains are sensitive to several DNA-damaging agents, but surprisingly both strains were more resistant than the wild-type strain to paraquat, menadione, and hydrogen peroxide. The atmA and atrA genes showed synthetic lethality emphasizing the cooperation between both enzymes and their consequent redundancy. The lack of atmA and atrA does not cause any significant virulence reduction in A. fumigatus in a neutropenic murine model of invasive pulmonary aspergillosis and in the invertebrate alternative model Galleria mellonela. Wild-type, ΔatmA, and ΔatrA populations that were previously transferred 10 times in minimal medium (MM) in the absence of voriconazole have not shown any significant changes in drug resistance acquisition. In contrast, ΔatmA and ΔatrA populations that similarly evolved in the presence of a subinhibitory concentration of voriconazole showed an ∼5–10-fold increase when compared to the original minimal inhibitory concentration (MIC) values. There are discrete alterations in the voriconazole target Cyp51A/Erg11A or cyp51/erg11 and/or Cdr1B efflux transporter overexpression that do not seem to be the main mechanisms to explain voriconazole resistance in these evolved populations. Taken together, these results suggest that genetic instability caused by ΔatmA and ΔatrA mutations can confer an adaptive advantage, mainly in the intensity of voriconazole resistance acquisition.