Immunization with lytic polysaccharide monooxygenase CbpD induces protective immunity against Pseudomonas aeruginosa pneumonia.

Autor: Askarian F; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093., Tsai CM; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093., Cordara G; Department of Chemistry, University of Oslo, N-0315 Oslo, Norway., Zurich RH; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093., Bjånes E; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093., Golten O; Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, N-1432 Ås, Norway., Vinther Sørensen H; Department of Chemistry, University of Oslo, N-0315 Oslo, Norway., Kousha A; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093., Meier A; Division of Critical Care, Department of Anesthesiology, University of California San Diego, La Jolla, CA 92037., Chikwati E; Department of Paraclinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, N-1432 Ås, Norway., Bruun JA; Proteomics and Metabolomics Core Facility, Department of Medical Biology, The Arctic University of Norway, N-9037 Tromsø, Norway., Ludviksen JA; Research Laboratory, Nordland Hospital, N-8005 Bodø, Norway., Choudhury B; Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093., Trieu D; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093.; School of Pharmacy, University of California San Francisco, San Francisco, CA 94143., Davis S; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093., Edvardsen PKT; Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, N-1432 Ås, Norway., Mollnes TE; Research Laboratory, Nordland Hospital, N-8005 Bodø, Norway.; Department of Immunology, University of Oslo Hospital, N-0424 Oslo, Norway.; Center of Molecular Inflammation Research, Norwegian University of Science and Technology, N-7491 Trondheim, Norway., Liu GY; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093., Krengel U; Department of Chemistry, University of Oslo, N-0315 Oslo, Norway., Conrad DJ; Division of Pulmonary, Critical Care and Sleep Medicine, University of California San Diego, La Jolla, CA 92037., Vaaje-Kolstad G; Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, N-1432 Ås, Norway., Nizet V; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093.; Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093.; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Jul 25; Vol. 120 (30), pp. e2301538120. Date of Electronic Publication: 2023 Jul 17.
DOI: 10.1073/pnas.2301538120
Abstrakt: Pseudomonas aeruginosa (PA) CbpD belongs to the lytic polysaccharide monooxygenases (LPMOs), a family of enzymes that cleave chitin or related polysaccharides. Here, we demonstrate a virulence role of CbpD in PA pneumonia linked to impairment of host complement function and opsonophagocytic clearance. Following intratracheal challenge, a PA ΔCbpD mutant was more easily cleared and produced less mortality than the wild-type parent strain. The x-ray crystal structure of the CbpD LPMO domain was solved to subatomic resolution (0.75Å) and its two additional domains modeled by small-angle X-ray scattering and Alphafold2 machine-learning algorithms, allowing structure-based immune epitope mapping. Immunization of naive mice with recombinant CbpD generated high IgG antibody titers that promoted human neutrophil opsonophagocytic killing, neutralized enzymatic activity, and protected against lethal PA pneumonia and sepsis. IgG antibodies generated against full-length CbpD or its noncatalytic M2+CBM73 domains were opsonic and protective, even in previously PA-exposed mice, while antibodies targeting the AA10 domain were not. Preexisting antibodies in PA-colonized cystic fibrosis patients primarily target the CbpD AA10 catalytic domain. Further exploration of LPMO family proteins, present across many clinically important and antibiotic-resistant human pathogens, may yield novel and effective vaccine antigens.
Databáze: MEDLINE