Heat-labile enterotoxin of human enterotoxigenic Escherichia coli (LTh)

Heat-labile enterotoxin (LT) is a major virulence factor produced by enterotoxigenic Escherichia coli (ETEC), which is a primary cause of diarrhea in travelers and children in low-income countries (UniProt P06717). The toxin is an AB5-type protein consisting of a catalytic A subunit and a pentameric B subunit that binds to GM1 ganglioside receptors on host cell surfaces (PubMed: 15175434). Detoxified LTh refers to human-derived LT variants, such as LT(R192G) or dLT, which have been genetically engineered to eliminate the ADP-ribosyltransferase activity responsible for toxicity while maintaining potent immunogenic properties (PubMed: 22431647). These detoxified forms are primarily utilized as mucosal adjuvants in vaccine development to stimulate robust secretory IgA and systemic IgG responses against ETEC (PubMed: 28919436). By enhancing the immune system's recognition of co-administered antigens, detoxified LTh plays a critical role in the design of oral vaccines like ETVAX, which aim to provide broad protection against ETEC-mediated disease (ClinicalTrials.gov: NCT02531802).

Other names

LTHeat-labile enterotoxindLTDetoxified heat-labile enterotoxinLT(R192G)LT-K63Escherichia coli heat-labile enterotoxinHuman heat-labile enterotoxin

The detoxified heat-labile enterotoxin (LTh) acts as a mucosal adjuvant by binding to GM1 ganglioside receptors on intestinal epithelial and immune cells via its B-subunit pentamer (PubMed: 15175434). In its detoxified form, such as the R192G mutant, the A-subunit's ability to ADP-ribosylate the Gs alpha protein is abolished, preventing the elevation of intracellular cAMP and the subsequent diarrheal response (PubMed: 22431647). However, the molecule remains highly immunogenic and facilitates the recruitment and activation of antigen-presenting cells, such as dendritic cells, thereby promoting the induction of both mucosal (IgA) and systemic (IgG) immune responses against co-administered or intrinsic antigens (PubMed: 28919436).