Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance.
Aspergillus fumigatus causes invasive aspergillosis, the most common life-threatening fungal disease of immuno-compromised humans. The treatment of disseminated infections with antifungal drugs, including echinocandin cell wall biosynthesis inhibitors, is increasingly challenging due to the rise of...
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Public Library of Science (PLoS)
2019-12-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008551&type=printable |
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| author | Patrícia Alves de Castro Ana Cristina Colabardini Adriana Oliveira Manfiolli Jéssica Chiaratto Lilian Pereira Silva Eliciane Cevolani Mattos Giuseppe Palmisano Fausto Almeida Gabriela Felix Persinoti Laure Nicolas Annick Ries Laura Mellado Marina Campos Rocha Michael Bromley Roberto Nascimento Silva Gabriel Scalini de Souza Flávio Vieira Loures Iran Malavazi Neil Andrew Brown Gustavo H Goldman |
| author_facet | Patrícia Alves de Castro Ana Cristina Colabardini Adriana Oliveira Manfiolli Jéssica Chiaratto Lilian Pereira Silva Eliciane Cevolani Mattos Giuseppe Palmisano Fausto Almeida Gabriela Felix Persinoti Laure Nicolas Annick Ries Laura Mellado Marina Campos Rocha Michael Bromley Roberto Nascimento Silva Gabriel Scalini de Souza Flávio Vieira Loures Iran Malavazi Neil Andrew Brown Gustavo H Goldman |
| author_sort | Patrícia Alves de Castro |
| collection | DOAJ |
| description | Aspergillus fumigatus causes invasive aspergillosis, the most common life-threatening fungal disease of immuno-compromised humans. The treatment of disseminated infections with antifungal drugs, including echinocandin cell wall biosynthesis inhibitors, is increasingly challenging due to the rise of drug-resistant pathogens. The fungal calcium responsive calcineurin-CrzA pathway influences cell morphology, cell wall composition, virulence, and echinocandin resistance. A screen of 395 A. fumigatus transcription factor mutants identified nine transcription factors important to calcium stress tolerance, including CrzA and ZipD. Here, comparative transcriptomics revealed CrzA and ZipD regulated the expression of shared and unique gene networks, suggesting they participate in both converged and distinct stress response mechanisms. CrzA and ZipD additively promoted calcium stress tolerance. However, ZipD also regulated cell wall organization, osmotic stress tolerance and echinocandin resistance. The absence of ZipD in A. fumigatus caused a significant virulence reduction in immunodeficient and immunocompetent mice. The ΔzipD mutant displayed altered cell wall organization and composition, while being more susceptible to macrophage killing and eliciting an increased pro-inflammatory cytokine response. A higher number of neutrophils, macrophages and activated macrophages were found in ΔzipD infected mice lungs. Collectively, this shows that ZipD-mediated regulation of the fungal cell wall contributes to the evasion of pro-inflammatory responses and tolerance of echinocandin antifungals, and in turn promoting virulence and complicating treatment options. |
| format | Article |
| id | doaj-art-1c17b4bbc41e485db85d83d1abc3b3f3 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2019-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-1c17b4bbc41e485db85d83d1abc3b3f32025-08-20T02:54:53ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042019-12-011512e100855110.1371/journal.pgen.1008551Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance.Patrícia Alves de CastroAna Cristina ColabardiniAdriana Oliveira ManfiolliJéssica ChiarattoLilian Pereira SilvaEliciane Cevolani MattosGiuseppe PalmisanoFausto AlmeidaGabriela Felix PersinotiLaure Nicolas Annick RiesLaura MelladoMarina Campos RochaMichael BromleyRoberto Nascimento SilvaGabriel Scalini de SouzaFlávio Vieira LouresIran MalavaziNeil Andrew BrownGustavo H GoldmanAspergillus fumigatus causes invasive aspergillosis, the most common life-threatening fungal disease of immuno-compromised humans. The treatment of disseminated infections with antifungal drugs, including echinocandin cell wall biosynthesis inhibitors, is increasingly challenging due to the rise of drug-resistant pathogens. The fungal calcium responsive calcineurin-CrzA pathway influences cell morphology, cell wall composition, virulence, and echinocandin resistance. A screen of 395 A. fumigatus transcription factor mutants identified nine transcription factors important to calcium stress tolerance, including CrzA and ZipD. Here, comparative transcriptomics revealed CrzA and ZipD regulated the expression of shared and unique gene networks, suggesting they participate in both converged and distinct stress response mechanisms. CrzA and ZipD additively promoted calcium stress tolerance. However, ZipD also regulated cell wall organization, osmotic stress tolerance and echinocandin resistance. The absence of ZipD in A. fumigatus caused a significant virulence reduction in immunodeficient and immunocompetent mice. The ΔzipD mutant displayed altered cell wall organization and composition, while being more susceptible to macrophage killing and eliciting an increased pro-inflammatory cytokine response. A higher number of neutrophils, macrophages and activated macrophages were found in ΔzipD infected mice lungs. Collectively, this shows that ZipD-mediated regulation of the fungal cell wall contributes to the evasion of pro-inflammatory responses and tolerance of echinocandin antifungals, and in turn promoting virulence and complicating treatment options.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008551&type=printable |
| spellingShingle | Patrícia Alves de Castro Ana Cristina Colabardini Adriana Oliveira Manfiolli Jéssica Chiaratto Lilian Pereira Silva Eliciane Cevolani Mattos Giuseppe Palmisano Fausto Almeida Gabriela Felix Persinoti Laure Nicolas Annick Ries Laura Mellado Marina Campos Rocha Michael Bromley Roberto Nascimento Silva Gabriel Scalini de Souza Flávio Vieira Loures Iran Malavazi Neil Andrew Brown Gustavo H Goldman Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance. PLoS Genetics |
| title | Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance. |
| title_full | Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance. |
| title_fullStr | Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance. |
| title_full_unstemmed | Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance. |
| title_short | Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance. |
| title_sort | aspergillus fumigatus calcium responsive transcription factors regulate cell wall architecture promoting stress tolerance virulence and caspofungin resistance |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008551&type=printable |
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