Molecular features of lipoprotein CD0873: A potential vaccine against the human pathogen Clostridioides difficile

William J. Bradshaw, Jean François Bruxelle, Andrea Kovacs-Simon, Nicholas J. Harmer, Claire Janoir, Severine Péchiné, K. Ravi Acharya, Stephen L. Michell

Research output: Contribution to journalArticle

Abstract

Clostridioides difficile is the primary cause of antibiotic-associated diarrhea and colitis, a healthcare-associated intestinal disease resulting in a significant fatality rate. Colonization of the gut is critical for C. difficile pathogenesis. 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 1.35-2.50 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 an effective component in a vaccine against C. difficile.

Original languageEnglish
Pages (from-to)15850-15861
Number of pages12
JournalThe Journal of biological chemistry
Volume294
Issue number43
Early online date16 Aug 2019
DOIs
Publication statusPublished - 25 Oct 2019

Keywords

  • ABC transporter
  • Clostridioides difficile
  • crystallography
  • microbiology
  • protein structure
  • tyrosine metabolism
  • vaccine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Cite this

Bradshaw, W. J., Bruxelle, J. F., Kovacs-Simon, A., Harmer, N. J., Janoir, C., Péchiné, S., Acharya, K. R., & Michell, S. L. (2019). Molecular features of lipoprotein CD0873: A potential vaccine against the human pathogen Clostridioides difficile. The Journal of biological chemistry, 294(43), 15850-15861. https://doi.org/10.1074/jbc.RA119.010120