The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Mismatch Repair <italic toggle="yes">MSH2</italic> Homolog Is Important for Virulence and Azole Resistance
ABSTRACT The genetic stability of every living organism depends on accurate DNA replication and repair systems. Here, we investigated the Aspergillus fumigatus MSH2 mismatch repair (MMR) gene MshA and how it impacts virulence and the evolution of azole resistance. We examined mshA gene variation in...
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American Society for Microbiology
2019
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oai:doaj.org-article:86d83744d786492d92b5986ec03a402b2021-11-15T15:22:26ZThe <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Mismatch Repair <italic toggle="yes">MSH2</italic> Homolog Is Important for Virulence and Azole Resistance10.1128/mSphere.00416-192379-5042https://doaj.org/article/86d83744d786492d92b5986ec03a402b2019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00416-19https://doaj.org/toc/2379-5042ABSTRACT The genetic stability of every living organism depends on accurate DNA replication and repair systems. Here, we investigated the Aspergillus fumigatus MSH2 mismatch repair (MMR) gene MshA and how it impacts virulence and the evolution of azole resistance. We examined mshA gene variation in 62 environmental and clinical A. fumigatus strains. We have observed 12 strains with variants (18.2%), and 8 strains among them showed missense variants. We demonstrated that A. fumigatus mshA null mutants are haploid and have conserved karyotypes with discrete gross chromosomal rearrangements. The ΔmshA strains are not sensitive to several DNA-damaging agents. The lack of mshA caused a significant reduction of virulence of A. fumigatus in a neutropenic murine model of invasive pulmonary aspergillosis and in the invertebrate alternative model Galleria mellonella. Wild-type and ΔmshA populations did not show any significant changes in drug resistance acquisition after they were transferred 10 times in minimal medium in the absence of any stress. However, these populations rapidly acquired virulence in the ΔmshA background and high levels of resistance to posaconazole in the presence of this drug (at least 200-fold-higher levels of resistance than those derived from the wild-type strain). Taken together, these results suggest that genetic instability caused by ΔmshA mutations can confer an adaptive advantage, mainly increasing posaconazole resistance and virulence acquisition. IMPORTANCE Invasive aspergillosis (IA) has emerged as one of the most common life-threatening fungal diseases in immunocompromised patients, with mortality rates as high as 90%. Systemic fungal infections such as IA are usually treated with triazoles; however, epidemiological research has shown that the prevalence of azole-resistant Aspergillus fumigatus isolates has increased significantly over the last decade. There is very little information about the importance of genomic stability for A. fumigatus population structure, azole resistance, and virulence. Here, we decided to investigate whether the mismatch repair system could influence A. fumigatus azole resistance and virulence, focusing on one of the components of this system, MSH2. Although the mutation frequency of mshA (the A. fumigatus MSH2 homologue) is low in environmental and clinical isolates, our results indicate that loss of mshA function can provide increased azole resistance and virulence when selected for. These results demonstrate the importance of genetic instability in A. fumigatus as a possible mechanism of evolving azole resistance and establishing fitness in the host.Thaila Fernanda dos ReisLilian Pereira SilvaPatrícia Alves de CastroRafaela Andrade do CarmoMarjorie Mendes MariniJosé Franco da SilveiraBeatriz Henriques FerreiraFernando RodriguesAbigail Lee LindAntonis RokasGustavo H. GoldmanAmerican Society for MicrobiologyarticleAspergillus fumigatusDNA repairMSH2azole resistancevirulenceMicrobiologyQR1-502ENmSphere, Vol 4, Iss 4 (2019) |
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DOAJ |
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DOAJ |
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EN |
| topic |
Aspergillus fumigatus DNA repair MSH2 azole resistance virulence Microbiology QR1-502 |
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Aspergillus fumigatus DNA repair MSH2 azole resistance virulence Microbiology QR1-502 Thaila Fernanda dos Reis Lilian Pereira Silva Patrícia Alves de Castro Rafaela Andrade do Carmo Marjorie Mendes Marini José Franco da Silveira Beatriz Henriques Ferreira Fernando Rodrigues Abigail Lee Lind Antonis Rokas Gustavo H. Goldman The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Mismatch Repair <italic toggle="yes">MSH2</italic> Homolog Is Important for Virulence and Azole Resistance |
| description |
ABSTRACT The genetic stability of every living organism depends on accurate DNA replication and repair systems. Here, we investigated the Aspergillus fumigatus MSH2 mismatch repair (MMR) gene MshA and how it impacts virulence and the evolution of azole resistance. We examined mshA gene variation in 62 environmental and clinical A. fumigatus strains. We have observed 12 strains with variants (18.2%), and 8 strains among them showed missense variants. We demonstrated that A. fumigatus mshA null mutants are haploid and have conserved karyotypes with discrete gross chromosomal rearrangements. The ΔmshA strains are not sensitive to several DNA-damaging agents. The lack of mshA caused a significant reduction of virulence of A. fumigatus in a neutropenic murine model of invasive pulmonary aspergillosis and in the invertebrate alternative model Galleria mellonella. Wild-type and ΔmshA populations did not show any significant changes in drug resistance acquisition after they were transferred 10 times in minimal medium in the absence of any stress. However, these populations rapidly acquired virulence in the ΔmshA background and high levels of resistance to posaconazole in the presence of this drug (at least 200-fold-higher levels of resistance than those derived from the wild-type strain). Taken together, these results suggest that genetic instability caused by ΔmshA mutations can confer an adaptive advantage, mainly increasing posaconazole resistance and virulence acquisition. IMPORTANCE Invasive aspergillosis (IA) has emerged as one of the most common life-threatening fungal diseases in immunocompromised patients, with mortality rates as high as 90%. Systemic fungal infections such as IA are usually treated with triazoles; however, epidemiological research has shown that the prevalence of azole-resistant Aspergillus fumigatus isolates has increased significantly over the last decade. There is very little information about the importance of genomic stability for A. fumigatus population structure, azole resistance, and virulence. Here, we decided to investigate whether the mismatch repair system could influence A. fumigatus azole resistance and virulence, focusing on one of the components of this system, MSH2. Although the mutation frequency of mshA (the A. fumigatus MSH2 homologue) is low in environmental and clinical isolates, our results indicate that loss of mshA function can provide increased azole resistance and virulence when selected for. These results demonstrate the importance of genetic instability in A. fumigatus as a possible mechanism of evolving azole resistance and establishing fitness in the host. |
| format |
article |
| author |
Thaila Fernanda dos Reis Lilian Pereira Silva Patrícia Alves de Castro Rafaela Andrade do Carmo Marjorie Mendes Marini José Franco da Silveira Beatriz Henriques Ferreira Fernando Rodrigues Abigail Lee Lind Antonis Rokas Gustavo H. Goldman |
| author_facet |
Thaila Fernanda dos Reis Lilian Pereira Silva Patrícia Alves de Castro Rafaela Andrade do Carmo Marjorie Mendes Marini José Franco da Silveira Beatriz Henriques Ferreira Fernando Rodrigues Abigail Lee Lind Antonis Rokas Gustavo H. Goldman |
| author_sort |
Thaila Fernanda dos Reis |
| title |
The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Mismatch Repair <italic toggle="yes">MSH2</italic> Homolog Is Important for Virulence and Azole Resistance |
| title_short |
The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Mismatch Repair <italic toggle="yes">MSH2</italic> Homolog Is Important for Virulence and Azole Resistance |
| title_full |
The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Mismatch Repair <italic toggle="yes">MSH2</italic> Homolog Is Important for Virulence and Azole Resistance |
| title_fullStr |
The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Mismatch Repair <italic toggle="yes">MSH2</italic> Homolog Is Important for Virulence and Azole Resistance |
| title_full_unstemmed |
The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Mismatch Repair <italic toggle="yes">MSH2</italic> Homolog Is Important for Virulence and Azole Resistance |
| title_sort |
<named-content content-type="genus-species">aspergillus fumigatus</named-content> mismatch repair <italic toggle="yes">msh2</italic> homolog is important for virulence and azole resistance |
| publisher |
American Society for Microbiology |
| publishDate |
2019 |
| url |
https://doaj.org/article/86d83744d786492d92b5986ec03a402b |
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