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

Fatemeh Askarian (), Satoshi Uchiyama, Helen Masson, Henrik Vinther Sørensen, Ole Golten, Anne Cathrine Bunæs, Sophanit Mekasha, Åsmund Kjendseth Røhr, Eirik Kommedal, Judith Anita Ludviksen, Magnus Ø. Arntzen, Benjamin Schmidt, Raymond H. Zurich, Nina M. van Sorge, Vincent G. H. Eijsink, Ute Krengel, Tom Eirik Mollnes, Nathan E. Lewis, Victor Nizet () and Gustav Vaaje-Kolstad ()
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Fatemeh Askarian: Norwegian University of Life Sciences (NMBU)
Satoshi Uchiyama: Department of Pediatrics, UC San Diego
Helen Masson: University of California, San Diego, School of Medicine
Henrik Vinther Sørensen: University of Oslo
Ole Golten: Norwegian University of Life Sciences (NMBU)
Anne Cathrine Bunæs: Norwegian University of Life Sciences (NMBU)
Sophanit Mekasha: Norwegian University of Life Sciences (NMBU)
Åsmund Kjendseth Røhr: Norwegian University of Life Sciences (NMBU)
Eirik Kommedal: Norwegian University of Life Sciences (NMBU)
Judith Anita Ludviksen: Nordland Hospital
Magnus Ø. Arntzen: Norwegian University of Life Sciences (NMBU)
Benjamin Schmidt: Department of Pediatrics, UC San Diego
Raymond H. Zurich: Department of Pediatrics, UC San Diego
Nina M. van Sorge: University Medical Center Utrecht, Utrecht University
Vincent G. H. Eijsink: Norwegian University of Life Sciences (NMBU)
Ute Krengel: University of Oslo
Tom Eirik Mollnes: Nordland Hospital
Nathan E. Lewis: Department of Pediatrics, UC San Diego
Victor Nizet: Department of Pediatrics, UC San Diego
Gustav Vaaje-Kolstad: Norwegian University of Life Sciences (NMBU)

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21473-0

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