Type II heat-labile enterotoxins: structure, function, and immunomodulatory properties

Abstract

The heat-labile enterotoxins (HLTs) of Escherichia coli and Vibrio cholerae are classified into two major types on the basis of genetic, biochemical, and immunological properties. Type I and Type II HLT have been intensively studied for their exceptionally strong adjuvant activities. Despite general structural similarities, these molecules, in intact or derivative (non-toxic) forms, display notable differences in their mode of immunomodulatory action. The molecular basis of these differences has remained largely uncharacterized until recently. This review focuses on the Type II HLTs and their immunomodulatory properties which depend largely on interactions with unique gangliosides and Toll-like receptors that are not utilized by the Type I HLTs.

Figure 1. Model for ganglioside-TLR cooperation for cell activation by LT-IIb-B₅

Upon binding of LT-IIb-B₅ to GD1a, GD1a facilitates the interaction of LT-IIb-B₅ with the TLR2/TLR1 signaling complex, which is recruited to lipid rafts. Induction of TLR2/TLR1 signaling for NF-κB activation by LT-IIb-B₅ occurs at the cell surface and requires the adaptor proteins TIRAP and MyD88, which colocalize with the LT-IIb-B₅ receptor complex (GD1a/TLR2/TLR1) (Hajishengallis et al., 2005a; Liang et al., 2009b; Liang et al., 2007a).

Figure 2. Differential and antagonistic effects on NF-κB activation by LT-IIb holotoxin and its B pentamer

LT-IIb-B₅ activates the TLR2/TLR1 heterodimer and induces NF-κB-dependent production of proinflammatorry cytokines (Liang et al., 2009a; Liang et al., 2007b). In contrast, the holotoxin does not interact with TLR2/TLR1 due to A subunit-dependent steric hindrance (Liang et al., 2009a; Liang et al., 2007b). However, upon GD1a binding and internalization of the holotoxin, the ADP-ribosyltransferase activity of its A subunit activates the Gsα component of adenylate cyclase (AC). This leads to elevation of intracellular cAMP, activation of cAMP-dependent protein kinase A (PKA), and inhibition of NF-κB-dependent transcription of proinflammatory cytokines (e.g., TNF-α) (Liang et al., 2007b).