Abstract
Cholera toxin B subunit (CTB), a non-toxic homopentameric component of Vibrio cholerae holotoxin, is an oral cholera vaccine antigen that induces an anti-toxin antibody response. Recently, we demonstrated that a recombinant CTB variant with a Lys-Asp-Glu-Leu (KDEL) endoplasmic reticulum retention motif (CTB-KDEL) exhibits colon mucosal healing effects that have therapeutic implications for inflammatory bowel disease (IBD). Herein, we investigated the feasibility of CTB-KDEL for the treatment of chronic colitis. We found that weekly oral administration of CTB-KDEL, dosed before or after the onset of chronic colitis, induced by repeated dextran sodium sulfate (DSS) exposure, could significantly reduce disease activity index scores, intestinal permeability, inflammation, and histological signs of chronicity. To address the consequences of immunogenicity, mice (C57BL/6 or C3H/HeJ strains) were pre-exposed to CTB-KDEL then subjected to DSS colitis and CTB-KDEL treatment. While the pre-dosing of CTB-KDEL elicited high-titer anti-drug antibodies (ADAs) of the immunoglobin A (IgA) isotype in the intestine of C57BL/6 mice, the therapeutic effects of CTB-KDEL were similar to those observed in C3H/HeJ mice, which showed minimal ADAs under the same experimental conditions. Thus, the immunogenicity of CTB-KDEL does not seem to impede the protein’s mucosal healing efficacy. These results support the development of CTB-KDEL for IBD therapy.
Highlights
The principal virulence factor of Vibrio cholerae is cholera toxin (CT), which is comprised of a toxic A subunit and a non-toxic homopentameric B subunit (CTB)
To characterize the therapeutic effect of Cholera toxin B subunit (CTB)-KDEL under chronic colitis conditions, we performed a chronic dextran sulfate sodium (DSS) colitis experiment in mice in which the animals were exposed to three cycles of seven-day
To characterize the therapeutic effect of CTB-KDEL under chronic colitis conditions, we performed a chronic DSS colitis experiment in mice in which the animals were exposed to three cycles of seven-day DSS exposure followed by 14 days of normal drinking water over 63 days
Summary
The principal virulence factor of Vibrio cholerae is cholera toxin (CT), which is comprised of a toxic A subunit and a non-toxic homopentameric B subunit (CTB). We have shown that a recombinant variant of CTB containing a KDEL endoplasmic reticulum (ER) retention motif (CTB-KDEL) has the ability to induce mucosal healing, facilitate colon epithelial wound repair, and enhance recovery from an acute dextran sulfate sodium (DSS) colitis model in mice [1,2] These effects were attributed to the addition of the C-terminal ER retention motif, KDEL, to CTB. The inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) arm of the UPR was indispensable for wound healing activity [2] These findings were corroborated in primary mouse colon epithelial cells, where CTB-KDEL induced an UPR, while CTB and the non-GM1 binding mutant G33D-CTB-KDEL failed to exhibit such an effect. These findings provide implications for the potential use of CTB-KDEL in the treatment of IBD
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