Antigenic mimicry of ubiquitin by the gut bacteriumBacteroides fragilis: a potential link with autoimmune disease

Abstract

SummaryUbiquitin is highly conserved across eukaryotes and is essential for normal eukaryotic cell function. The bacterium Bacteroides fragilis is a member of the normal human gut microbiota, and the only bacterium known to encode a homologue of eukaryotic ubiquitin. The B. fragilis gene sequence indicates a past horizontal gene transfer event from a eukaryotic source. It encodes a protein (BfUbb) with 63% identity to human ubiquitin which is exported from the bacterial cell. The aim of this study was (i) to determine if there was antigenic cross‐reactivity between B. fragilis ubiquitin and human ubiquitin and (ii) to determine if humans produced antibodies to BfUbb. Molecular model comparisons of BfUbb and human ubiquitin predicted a high level (99·8% confidence) of structural similarity. Linear epitope mapping identified epitopes in BfUbb and human ubiquitin that cross‐react. BfUbb also has epitope(s) that do not cross‐react with human ubiquitin. The reaction of human serum (n = 474) to BfUbb and human ubiquitin from the following four groups of subjects was compared by enzyme‐linked immunosorbent assay (ELISA): (1) newly autoantibody‐positive patients, (2) allergen‐specific immunoglobulin (Ig)E‐negative patients, (3) ulcerative colitis patients and (4) healthy volunteers. We show that the immune system of some individuals has been exposed to BfUbb which has resulted in the generation of IgG antibodies. Serum from patients referred for first‐time testing to an immunology laboratory for autoimmune disease are more likely to have a high level of antibodies to BfUbb than healthy volunteers. Molecular mimicry of human ubiquitin by BfUbb could be a trigger for autoimmune disease.

Correlation between Antibodies to Bacterial Lipopolysaccharides and Barrier Proteins in Sera Positive for ASCA and ANCA

“…In fact, in addition to LPS from gut pathogens, additional factors, including dietary components, in particular, sugars, gluten, yeast, and some xenobiotics have been shown to be directly or indirectly responsible for the alteration of the intestinal epithelial tight junction and the induction of intestinal inflammation [31,[64][65][66][67][68][69][70][71][72].…”

Higher prevalence ofBacteroides fragilisin Crohn’s disease exacerbations and strain-dependent increase of epithelial resistance

“…Bft and Ubb are two B. fragilis proteins, which have previously been shown to affect the host via direct and indirect interactions, respectively. 21,27 The metalloprotease Bft has been shown to disrupt the epithelial barrier by cleaving the adherens junctions protein E-cadherin in vitro, 27 whereas Ubb was found to mimic human Ubb and led to antibody formation in vivo. 21 These two compounds were therefore considered of interest and detected in the fecal metagenomes of CD patients.…”

“…fragilis is a Gram-negative commensal of the phylum Bacteroidetes and some strains secrete various virulence factors, such as an eukaryotic-like ubiquitin (Ubb) and B. fragilis toxin (Bft; fragilysin). 21,22 It is yet unclear whether these virulence factors contribute to CD exacerbations.…”

Host-microbiome protein-protein interactions reveal mechanisms in human disease

“…Protein-protein interactions (PPIs) have revealed the mechanisms by which pathogens interact with host tissue through in-depth structural studies of individual proteins [3][4][5] , as well as large-scale whole-organism interaction screens 6,7 . Although there are canonical microbe-associated patterns (MAMPs) that directly trigger host-signaling pathways through pattern recognition receptors present on epithelial and immune tissues 8 , such as flagellin with Toll-like receptor 5 (TLR5), several recent observations have further underscored a role for commensal-host PPIs in health: An integrase encoded by several Bacteroides species binds human islet-specific glucose-6-phosphatase-catalyticsubunit-related protein (IGRP) thereby protecting against colitis 9 ; a protease secreted by Enterococcus faecalis binds incretin hormone glucagon-like peptide 1 (GLP-1), a therapeutic target for type 2 diabetes (T2D) 10 ; and a slew of ubiquitin mimics encoded by both pathogens 11 and gut commensals 12 play a role in modulating membrane trafficking.…”