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Molecular features of lipoprotein CD0873 – a potential vaccine against the human pathogen Clostridioides difficile

DOI: 10.1074/jbc.RA119.010120 DOI Help

Authors: William J. Bradshaw (Structural Genomics Consortium, University of Oxford) , Jean-françois Bruxelle (Université Paris-Saclay) , Andrea Kovacs-simon (University of Exeter) , Nicholas J. Harmer (University of Exeter) , Claire Janoir (Université Paris-Sud) , Severine Péchiné (Université Paris-Saclay) , K. Ravi Acharya (University of Bath) , Stephen L. Michell (University of Exeter)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: August 2019
Diamond Proposal Number(s): 12342 , 17212

Abstract: Clostridioides difficile is the primary cause of antibiotic-associated diarrhoea and colitis, a healthcare-associated intestinal disease resulting in a significant fatality rate. Colonization of the gut is critical for C. difficile pathogenesis, and the bacterial molecules essential for efficient colonization therefore offer great potential as vaccine candidates. Here we present findings demonstrating that the C. difficile immunogenic lipoprotein CD0873 plays a critical role in pathogen success in vivo. We found that in a dixenic colonization model, a CD0873-positive strain of C. difficile significantly outcompeted a CD0873-negative strain. Immunization of mice with recombinant CD0873 prevented long-term gut colonization and was correlated with a strong secretory IgA immune response. We further present high-resolution crystal structures of CD0873, at 1.80-2.50 Å resolutions, offering a first view of the ligand-binding pocket of CD0873 and provide evidence that this lipoprotein adhesin is part of a tyrosine import system, an amino acid key in C. difficile infection. These findings suggest that CD0873 could serve as a effective component in a vaccine against C. difficile.

Journal Keywords: Tyrosine metabolism; Clostridioides difficile; microbiology; protein structure; vaccine; ABC transporter; crystallography

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

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