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 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 atmA and atrA 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, atmA, and atrA 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, atmA and atrA 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 vor...

Source: G3: Genes Genomes Genetics - January 4, 2018 Category: Genetics & Stem Cells Authors: dos Reis, T. F., Silva, L. P., de Castro, P. A., Almeida de Lima, P. B., do Carmo, R. A., Marini, M. M., da Silveira, J. F., Ferreira, B. H., Rodrigues, F., Malavazi, I., Goldman, G. H. Tags: Investigations Source Type: research