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The lytic polysaccharide monooxygenase CbpD promotes Pseudomonas aeruginosa virulence in systemic infection

Permanent lenke
https://hdl.handle.net/10037/20643
DOI
https://doi.org/10.1038/s41467-021-21473-0
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article.pdf (4.116Mb)
Publisert versjon (PDF)
Dato
2021-02-23
Type
Journal article
Tidsskriftartikkel
Peer reviewed

Forfatter
Askarian, Fatemeh; Uchiyama, Satoshi; Masson, Helen; Sørensen, Henrik Vinther; Golten, Ole; Bunæs, Anne Cathrine; Mekasha, Sophanit; Røhr, Åsmund Kjendseth; Kommedal, Eirik Garpestad; Ludviksen, Judith Anita; Arntzen, Magnus Øverlie; Schmidt, Benjamin; Zurich, Raymond H.; Van Sorge, Nina M.; Eijsink, Vincent; Krengel, Ute; Mollnes, Tom Eirik; Lewis, Nathan E.; Nizet, Victor; Vaaje-Kolstad, Gustav
Sammendrag
The recently discovered lytic polysaccharide monooxygenases (LPMOs), which cleave polysaccharides by oxidation, have been associated with bacterial virulence, but supporting functional data is scarce. Here we show that CbpD, the LPMO of Pseudomonas aeruginosa, is a chitin-oxidizing virulence factor that promotes survival of the bacterium in human blood. The catalytic activity of CbpD was promoted by azurin and pyocyanin, two redox-active virulence factors also secreted by P. aeruginosa. Homology modeling, molecular dynamics simulations, and small angle X-ray scattering indicated that CbpD is a monomeric tri-modular enzyme with flexible linkers. Deletion of cbpD rendered P. aeruginosa unable to establish a lethal systemic infection, associated with enhanced bacterial clearance in vivo. CbpD-dependent survival of the wild-type bacterium was not attributable to dampening of pro-inflammatory responses by CbpD ex vivo or in vivo. Rather, we found that CbpD attenuates the terminal complement cascade in human serum. Studies with an active site mutant of CbpD indicated that catalytic activity is crucial for virulence function. Finally, profiling of the bacterial and splenic proteomes showed that the lack of this single enzyme resulted in substantial re-organization of the bacterial and host proteomes. LPMOs similar to CbpD occur in other pathogens and may have similar immune evasive functions.
Forlag
Nature Research
Sitering
Askarian F, Uchiyama S, Masson, Sørensen HV, Golten O, Bunæs AC, Mekasha S, Røhr ÅK, Kommedal E, Ludviksen, Arntzen M, Schmidt, Zurich, Van Sorge NM, Eijsink V, Krengel U, Mollnes, Lewis NE, Nizet V, Vaaje-Kolstad G. The lytic polysaccharide monooxygenase CbpD promotes Pseudomonas aeruginosa virulence in systemic infection. Nature Communications. 2021
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Copyright 2021 The Author(s)

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