title: Activation of Bacteroides fragilis toxin by a novel bacterial protease contributes to anaerobic sepsis in mice.
abstract: Bacteroides fragilis is the leading cause of anaerobic bacteremia and sepsis. Enterotoxigenic strains that produce B. fragilis toxin (BFT, fragilysin) contribute to colitis and intestinal malignancy, yet are also isolated in bloodstream infection. It is not known whether these strains harbor unique genetic determinants that confer virulence in extra-intestinal disease. We demonstrate that BFT contributes to sepsis in mice, and we identify a B. fragilis protease called fragipain (Fpn) that is required for the endogenous activation of BFT through the removal of its auto-inhibitory prodomain. Structural analysis of Fpn reveals a His-Cys catalytic dyad that is characteristic of C11-family cysteine proteases that are conserved in multiple pathogenic Bacteroides spp. and Clostridium spp. Fpn-deficient, enterotoxigenic B. fragilis has an attenuated ability to induce sepsis in mice; however, Fpn is dispensable in B. fragilis colitis, wherein host proteases mediate BFT activation. Our findings define a role for B. fragilis enterotoxin and its activating protease in the pathogenesis of bloodstream infection, which indicates a greater complexity of cellular targeting and activity of BFT than previously recognized. The expression of fpn by both toxigenic and nontoxigenic strains suggests that this protease may contribute to anaerobic sepsis in ways that extend beyond its role in toxin activation. It could thus potentially serve as a target for disease modification.
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, Illinois, USA.|Interdisciplinary Scientist Training Program, University of Chicago, Chicago, Illinois, USA.
authors.forename: Vivian M
authors.initials: VM
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Herrou
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, Illinois, USA.|Interdisciplinary Scientist Training Program, University of Chicago, Chicago, Illinois, USA.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Hecht
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Teoh
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois, USA.|Present address: Departments of Pathology and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Crosson
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, Illinois, USA.|of Pediatrics, University of Chicago, Chicago, Illinois, USA.
authors.forename: Juliane
authors.initials: J
authors.lastname: Bubeck Wardenburg
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000378:metabolism / Q000382:microbiology; D001421:Bacteria, Anaerobic; D001426:Bacterial Proteins / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism; D001442:Bacteroides Infections / Q000378:metabolism* / Q000382:microbiology; D001441:Bacteroides fragilis; D015153:Blotting, Western; D003092:Colitis / Q000378:metabolism* / Q000382:microbiology; D018360:Crystallography, X-Ray; D057056:Cysteine Proteases / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D018805:Sepsis / Q000378:metabolism* / Q000382:microbiology; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D057056:Cysteine Proteases; C405031:Bacteroides fragilis toxin; D008666:Metalloendopeptidases; C091198:fragilysin