Labile toxin

Further studies concerning the activity of glycodendrons containing two or four peripheral GMjOS against the E. coli heat-labile toxin (LTBh) B-pentamer have been similarly described (Fig. 43).313... 

EAggEC children in the developing world 20-48 h persistent FliC - inflammation EAST-1 - guanylate cyclase -t secretion heat-labile toxin Ca2+-dependent actin phosphorylation cytoskeletal damage Pet - histopathologic effects on human intestinal mucosa... 

Dallas WS, Falkow S Amino acid sequence homology between cholera toxin and Escherichia coli heat-labile toxin. Nature 1980 288 499-501. 

Baldwin TJ, Knutton S, Sellers L, Hernandez HA, Aitken A, Williams PH Enteroaggregative Escherichia coli strains secrete a heat-labile toxin antigenically related to E. coli hemolysin. Infect Immun 1992,60 2092-2095. 

LT = Heat-labile toxin ST = heat-stable toxin. 

Enterotoxigenic E. coli B subunits of the heat labile toxin (LTB) Maize seed Elicited neutralizing antibodies. Immunogenic when administered orally. Serum and secretory immune responses in humans. Partially protective in mouse gut fluid assay. 27-29, 89, unpublished data... 

Two of the most widely spread and well-studied enterotoxigenic forms of bacterial diarrhea are ETEC and Vibrio cholerae. The toxins they produce, labile toxin (LT) and cholera toxin (CT) respectively, are very similar in primary sequence, structure, and mechanism of action [72]. They are homologous multi-subunit proteins in which the non-toxic B subunit mediates GMj ganglioside binding, and thus are candidates for vaccines that can neutralize toxin activity. 

ETEC is capable of producing two plasmid-mediated enterotoxins heat-labile toxin and heat-stable toxin. The net effect of either toxin on the mucosa is production of a cholera-like secretory diarrhea. 

Moravec, T., Schmidt, M.A., Herman, E.M., and Woodford-Thomas, T. (2007). Production of Escherichia coli heat labile toxin (LT) B subunit in soybean seed and analysis of its immunogenicity as an oral vaccine. Vaccine 25(9) 1647-1657. 

Cholera Toxin (CT) and E. coli Heat-Labile Toxin (LT)... 

Beyer, A., Wang, K., Umble, A.N., Wolt, J.D., and Cunnick, J.E. (2007). Low-dose exposure and immunogenicity of transgenic maize expressing the Escherichia coli heat-labile toxin B subunit. Environ. Health Perspect. 115(3) 354-360. 

Influenza hemagglutinin and neuraminidase (when used in combination with heat-labile toxin (HLT) Good response in presence of HLT 219... 

Gluck, U., Gebbers, J. O., and Gluck, R. (1999), Phase I evaluation of intranasal viro-somal influenza vaccine with and without Escherichia coli heat-labile toxin in adult volunteers, J. Virol., 73,7780-7786. 

The current status of adjuvanted influenza vaccines has been reviewed (26). The authors concluded that the vaccine produces a higher titer of antibodies than non-adjuvanted or virosomal vaccines. Local reactions occur more often, but are mild and transient. The results of a trial with two doses of an intranasally administered inactivated virosome-formulated influenza vaccine containing Escherichia coli heat-labile toxin as a mucosal adjuvant in 106 volunteers aged 33-63 years have been reported (27). About 50% of vaccinees had local adverse reactions (44% after the first dose and 54% after the second dose) or systemic adverse reactions (48 and 46%) after administration of the vaccine. Rhinorrhea, sneezing, and headache were the most common reactions they were mild and transient and resolved within 24-48 hours. No febrile reactions were associated with immunization. Between 77 and 92% of vaccinees developed protective hemagglutination inhibition antibody titers against the two influenzae A strains of the vaccine, whereas protective antibody titers against the B strain of the vaccine were achieved in only 49-58%. 

Gluck R, Mischler R, Durrer P, Furer E, Lang AB, Herzog C, Cryz SJ Jr. Safety and immunogenicity of intranasally administered inactivated trivalent virosome-formulated influenza vaccine containing Escherichia coli heat-labile toxin as a mucosal adjuvant J Infect Dis 2000 181(3) 1129-32. 

Douce G, Turcotte C, Cropley I, etal. (1995) Mutants of Escherichia coli heat-labile toxin lacking ADP-ribosyltransferase activity act as nontoxic, mucosal adjuvants. In Proc. Natl. Acad. Sci. USA 92 1644-1648. 

Fig. 1. The active sites of PT SI and of the A subunits of diphtheria toxin and Escherichia coii heat labile toxin. The thin lines represent the carbon backbones. Only those (3 strands and a helices that are relevant for the active-site geometry are shown. The side chains of residues involved in the enzyme activity, especially those of the catalytic Glu and His residues, are represented by the thick lines. The a2 helix present in PT (top) and coii heat labile toxin (LT, right) is completely missing in diphtheria toxin (DT, left)...

Cholera toxin and E. call heat-labile toxin ADP-ribosylate the a-subunit of trimeric G-proteins (Gj) so that they are unable to hydrolyze GTP (Casey and Gilman, 1988 Neer and Claphan, 1988). As a result, the adenylate cyclase stays in a persistently active state. The toxin is taken up from the apical pole of the enterocytes, whereas the adenylate cyclase is located at the basolateral side. Since membrane glycolipids such as the toxin receptor (ganglioside GMi) tend not to cross tight junctions, it is unlikely that the toxin reaches the basolateral side by lateral diffusion. Most likely it enters the cytosol and diffuses to the target which is also located at the cytosolic side of the membrane. 

Clostridium perfringens has at least six serotypes and produces over 20 toxins. Epsilon toxin, along with alpha, beta, and iota toxins, is dermonecrotic and lethal. It is produced by some strains of type B and especially type D as a protoxin that is then converted to an active, mature, heat-labile toxin. The resulting toxin binds to cell membranes and forms a membrane complex that promotes the efflux of intracellular potassium. Because the usual route of entry is the gastrointestinal tract, the resulting pathology is an increase in intestinal permeability that enhances absorption of more toxin and ensures systemic toxemia. In animals, increased vascular permeability leads to enterotoxemia, pulpy kidney , altered hepatic function, and cerebral edema and necrosis. 

VI. Victor, T DuToit, R., Van Zyl, J., Bester, A. J., and Van Helden, P. D., Improved method for the routine identification of toxigenic Escherichia coli by DNA amplification of a conserved region of the heat-labile toxin A subunit. J. Clin. Microbiol. 29, 158-161 (1991). 

The B subunit of the E. coli heat-labile toxin binds to the brush border of intestinal epithelial cells in a highly specific, lectinlike manner. Uptake of this toxin and transcytosis to the basolateral side of the enterocytes was observed both in vivo (63) and in vitro (64). 

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