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Targeted Disruption of Non-Ribosomal Peptide Synthetase pes3 Augments the Virulence of Aspergillus fumigatus

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  • Karen O'Hanlon, Ireland
  • Timothy Cairns, Department of Microbiology, Imperial College London, United Kingdom
  • Deirdre Stack, Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Co, Ireland
  • Markus Schrettl, Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Co, Ireland
  • Elaine M Bignell, Department of Microbiology, United Kingdom
  • Kevin Kavanagh, Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Ireland
  • Sinéad M Miggin, Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Ireland
  • Grainne O'Keeffe, Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Ireland
  • Thomas O Larsen, Center for Microbial Biotechnology, DTU Systems Biology, Technical University of Denmark, Denmark
  • Sean Doyle, Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Ireland
  • Afgrødeøkologi og Produktkvalitet
Nonribosomal peptide synthesis (NRPS) is a documented virulence factor for the opportunistic pathogen Aspergillus fumigatus and other fungi. Secreted or intracellularly located NRP products include the toxic molecule gliotoxin and the iron-chelating siderophores triacetylfusarinine C and ferricrocin. No structural or immunologically relevant NRP products have been identified in the organism. We investigated the function of the largest gene in A. fumigatus, which encodes the NRP synthetase Pes3 (AFUA_5G12730), by targeted gene deletion and extensive phenotypic analysis. It was observed that in contrast to other NRP synthetases, deletion of pes3 significantly increases the virulence of A. fumigatus, whereby the pes3 deletion strain (A. fumigatus {Delta}pes3) exhibited heightened virulence (increased killing) in invertebrate (P < 0.001) and increased fungal burden (P = 0.008) in a corticosteroid model of murine pulmonary aspergillosis. Complementation restored the wild-type phenotype in the invertebrate model. Deletion of pes3 also resulted in increased susceptibility to the antifungal, voriconazole (P < 0.01), shorter germlings, and significantly reduced surface β-glucan (P = 0.0325). Extensive metabolite profiling revealed that Pes3 does not produce a secreted or intracellularly stored NRP in A. fumigatus. Macrophage infections and histological analysis of infected murine tissue indicate that {Delta}pes3 heightened virulence appears to be mediated by aberrant innate immune recognition of the fungus. Proteome alterations in A. fumigatus {Delta}pes3 strongly suggest impaired germination capacity. Uniquely, our data strongly indicate a structural role for the Pes3-encoded NRP, a finding that appears to be novel for an NRP synthetase
Original languageEnglish
JournalInfection and Immunity
Volume79
Issue10
Pages (from-to)3978-3992
Number of pages14
ISSN0019-9567
DOIs
Publication statusPublished - Oct 2011

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