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Review
. 2007 Oct;6(5):821-34.
doi: 10.1586/14760584.6.5.821.

Cholera toxin, LT-I, LT-IIa and LT-IIb: the critical role of ganglioside binding in immunomodulation by type I and type II heat-labile enterotoxins

Terry D Connell  1
Affiliations
Review

Cholera toxin, LT-I, LT-IIa and LT-IIb: the critical role of ganglioside binding in immunomodulation by type I and type II heat-labile enterotoxins

Terry D Connell. Expert Rev Vaccines. 2007 Oct.

Abstract

The heat-labile enterotoxins expressed by Vibrio cholerae (cholera toxin) and Escherichia coli (LT-I, LT-IIa and LT-IIb) are potent systemic and mucosal adjuvants. Coadministration of the enterotoxins with a foreign antigen produces an augmented immune response to that antigen. Although each enterotoxin has potent adjuvant properties, the means by which the enterotoxins induce various immune responses are distinctive for each adjuvant. Various mutants have been engineered to dissect the functions of the enterotoxins required for their adjuvanticity. The capacity to strongly bind to one or more specific ganglioside receptors appears to drive the distinctive immunomodulatory properties associated with each enterotoxin. Mutant enterotoxins with ablated or altered ganglioside-binding affinities have been employed to investigate the role of gangliosides in enterotoxin-dependent immunomodulation.

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Figures

Fig. 1
Fig. 1
Pathways for the biosynthesis of the common a-, b-, and c-series of gangliosides. Synthesis of the various gangliosides involves the sequential activities of two types of enzymes: sialyltransferases (noted in solid lines) and glycosyltransferases (noted in dotted lines). Modified from - The Lipid Library. “Gangliosides: Structure, occurrence, biology and analysis”. http://www.lipidlibrary.co.uk/Lipids/gang/. Copyright of W.W. Christie and/ where stated The Oily Press Ltd or others. Mr. Christie can be contacted by email at William.Christie@scri.ac.uk.
Fig. 2
Fig. 2
Ribbon diagrams of the crystal structures of CT [135], LT-I [135-137], and LT-IIb [138]. The A polypeptide, containing the catalytically-active A1 chain, is non-covalently bound to the B pentamer by interactions between the extended alpha helix of the A2 chain. A proteolytically-sensitive site is located in a site between the A1 and A2 chains bounded by two cysteines which form a disulfide bond. The five ganglioside binding pockets are located on the opposite side of the B pentamer in respect to the A polypeptide. Figure is modified from [139].
Fig. 3
Fig. 3
Model of the multimolecular complex formed by cooperative binding of LT-IIbB to GD1a and TLR2. After formation, the multimolecular complex is recruited into lipid rafts. Induction of TLR2 occurs on the cell surface and requires TIRAP, an adaptor protein, which co-localizes to the LT-IIbB/GD1a//TLR2 complex. Figure was originally published in [134].
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References

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