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Antigenic mimicry of ubiquitin by the gut bacterium Bacteroides fragilis: a potential link with autoimmune disease.

ABSTRACT: Ubiquitin 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.

SUBMITTER: Stewart L

PROVIDER: S-EPMC6194340 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Antigenic mimicry of ubiquitin by the gut bacterium Bacteroides fragilis: a potential link with autoimmune disease.

Stewart L L D M Edgar J J Blakely G G Patrick S S

Clinical and experimental immunology 20180917 2

Ubiquitin 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 ...[more]

PMID: 30076785

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Project description:Enterohemorrhagic E. coli (EHEC) is associated with severe gastrointestinal disease. Upon entering the gastrointestinal tract, EHEC is exposed to a fluctuating environment and a myriad of other bacterial species. To establish an infection, EHEC strains have to modulate their gene expression according to the GI tract environment. In order to explore the interspecies interactions between EHEC and an human intestinal commensal, the global gene expression profile was determined of EHEC O103:H25 (EHEC NIPH-11060424) co-cultured with B. thetaiotaomicron (CCUG 10774) or grown in the presence of spent medium from B. thetaiotaomicron. Microarray analysis revealed that approximately 1% of the EHEC NIPH-11060424 genes were significantly up-regulated both in co-culture (30 genes) and in the presence of spent medium (44 genes), and that the affected genes differed between the two conditions. In co-culture, genes encoding structural components of the type three secretion system were among the most affected genes with an almost 4-fold up-regulation, while the most affected genes in spent medium were involved in chemotaxis and were more than 3-fold up-regulated. The operons for type three secretion system (TTSS) are located on the Locus of enterocyte effacement (LEE) pathogenicity island, and qPCR showed that genes of all five operons (LEE1-LEE5) were up-regulated. Moreover, an increased adherence to HeLa cells was observed in EHEC NIPH-11060424 exposed to B. thetaiotaomicron. Expression of stx2 genes, encoding the main virulence factor of EHEC, was down-regulated in both conditions (co-culture/spent medium). These results show that expression of EHEC genes involved in colonization and virulence is modulated in response to direct interspecies contact between cells, or to diffusible factors released from B. thetaiotaomicron. Such interspecies interactions could allow the pathogen to recognize its predilection site and modulate its behaviour accordingly, thus increasing the efficiency of colonization of the colon mucosa, facilitating its persistence and increasing its virulence potential.

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Dataset Information

Antigenic mimicry of ubiquitin by the gut bacterium Bacteroides fragilis: a potential link with autoimmune disease.

Publications

Antigenic mimicry of ubiquitin by the gut bacterium Bacteroides fragilis: a potential link with autoimmune disease.

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