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

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dc.citation.issue1
dc.citation.volume8
dc.contributor.authordos Reis, Thaila Fernanda
dc.contributor.authorSilva, Lilian Pereira
dc.contributor.authorde Castro, Patricia Alves
dc.contributor.authorAlmeida de Lima, Pollyne Borborema
dc.contributor.authordo Carmo, Rafaela Andrade [UNIFESP]
dc.contributor.authorMarini, Marjorie Mendes [UNIFESP]
dc.contributor.authorda Silveira, Jose Franco [UNIFESP]
dc.contributor.authorFerreira, Beatriz Henriques
dc.contributor.authorRodrigues, Fernando
dc.contributor.authorMalavazi, Iran
dc.contributor.authorGoldman, Gustavo H.
dc.coverageBethesda
dc.date.accessioned2020-07-02T18:52:12Z
dc.date.available2020-07-02T18:52:12Z
dc.date.issued2018
dc.description.abstractGenetic 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 Delta atmA and Delta 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, Delta atmA, and Delta 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, Delta atmA and Delta atrA populations that similarly evolved in the presence of a subinhibitory concentration of voriconazole showed an similar to 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 Delta atmA and Delta atrA mutations can confer an adaptive advantage, mainly in the intensity of voriconazole resistance acquisition.en
dc.description.affiliationUniv Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Ribeirao Preto, Brazil
dc.description.affiliationUniv Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, BR-04023062 Sao Paulo, Brazil
dc.description.affiliationUniv Minho, Life & Hlth Sci Res Inst ICVS, Sch Med, Braga, Portugal
dc.description.affiliationICVS 3Bs PT Govt Associate Lab Braga Guimaraes, P-4710057 Braga, Portugal
dc.description.affiliationUniv Fed Sao Carlos, Dept Genet & Evolucao, Ctr Ciencias Biol & Saude, BR-13565905 Sao Paulo, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, BR-04023062 Sao Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo
dc.description.sponsorshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil
dc.description.sponsorshipNorthern Portugal Regional Operational Program (NORTE) under the Portugal Partnership Agreement through the European Regional Development Fund [NORTE-01-0145-FEDER-000013]
dc.format.extent265-278
dc.identifierhttp://dx.doi.org/10.1534/g3.117.300265
dc.identifier.citationG3-Genes Genomes Genetics. Bethesda, v. 8, n. 1, p. 265-278, 2018.
dc.identifier.doi10.1534/g3.117.300265
dc.identifier.fileWOS000419333800024.pdf
dc.identifier.issn2160-1836
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/53943
dc.identifier.wosWOS:000419333800024
dc.language.isoeng
dc.publisherGenetics Society America
dc.relation.ispartofG3-Genes Genomes Genetics
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectAspergillus fumigatusen
dc.subjectATMen
dc.subjectATRen
dc.subjectazolesen
dc.subjectDNA damageen
dc.subjectGalleria mellonelaen
dc.subjectgenetic instabilityen
dc.subjectPFGEen
dc.subjectvirulenceen
dc.subjectvoriconazoleen
dc.titleThe Influence of Genetic Stability on Aspergillus fumigatus Virulence and Azole Resistanceen
dc.typeinfo:eu-repo/semantics/article
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