uroguanylin and Escherichia-coli-Infections

Some E. coli cause diarrhea by elaborating heat-labile and heat-stable (ST) enterotoxins which stimulate intestinal secretion. E. coli ST's are small peptides which bind to intestinal luminal epithelial cell receptors. The ST receptor, one of a family of receptor-cyclases called guanylyl cyclase C (GC-C), is a membrane spanning protein containing an extracellular binding domain and intracellular protein kinase and catalytic domains. The intestine synthesizes and secretes homologous peptides, guanylin and uroguanylin. The kidney also synthesizes uroguanylin. ST, guanylin or uroguanylin binding to GC-C results in increased cGMP, phosphorylation of the CFTR Cl- channel and secretion. Proguanylin and prouroguanylin circulate in blood and bind to receptors in intestine, kidney, liver, brain etc. In the kidney, they stimulate the excretion of Na+ and K+. Study of GC-C "knock-out" mice reveal that GC-C is important to intestinal salt and water secretion, duodenal bicarbonate secretion, recovery from CCl4-induced liver injury, and to intestinal polyp formation in Min mice lacking GC-C.

Topics: Amino Acid Sequence; Animals; Bacterial Toxins; Diarrhea; Enterotoxins; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Gastrointestinal Hormones; Guanylate Cyclase; Humans; Intestinal Polyps; Mice; Mice, Knockout; Models, Biological; Molecular Sequence Data; Natriuretic Peptides; Peptides; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide

Enterotoxigenic Escherichia coli (ETEC) causes diarrhoea by secreting enterotoxins into the small intestine. Human ETEC strains may secrete any combination of three enterotoxins: the heat-labile toxin (LT) and the heat-stable toxins (ST), of which there are two variants, called human ST (STh) and porcine ST (STp). Strains expressing STh, either alone or in combination with LT and/or STp, are among the four most important diarrhoea-causing pathogens affecting children in low- and middle-income countries. ST is therefore an attractive target for ETEC vaccine development. To produce a safe ST-based vaccine, several challenges must be solved. ST must be rendered immunogenic and non-toxic, and antibodies elicited by an ST vaccine should neutralize ST but not cross-react with the endogenous ligands uroguanylin and guanylin. Virus-like particles (VLPs) tend to be highly immunogenic and are increasingly being used as carriers for presenting heterologous antigens in new vaccines. In this study, we have coupled native STh and the STh-A14T toxoid to the coat protein of Acinetobacter phage AP205 by using the SpyCatcher system and immunized mice with these VLPs without the use of adjuvants. We found that both STs were efficiently coupled to the VLP, that both the STh and STh-A14T VLPs were immunogenic in mice, and that the resulting serum antibodies could completely neutralize the toxic activities of native STh. The serum antibodies showed a high degree of immunological cross-reaction to STp, while there was little or no unwanted cross-reaction to uroguanylin and guanylin. Moreover, compared to native STh, the STh-A14T mutation did not seem to negatively impact the immunogenicity of the construct or the neutralizing ability of the resulting sera. Taken together, these findings demonstrate that VLPs are suitable carriers for making STs immunogenic, and that the STh-A14T-coupled AP205 VLP represents a promising ETEC vaccine candidate.

Topics: Acinetobacter; Animals; Antibodies, Bacterial; Antibodies, Neutralizing; Antigens, Bacterial; Bacterial Toxins; Bacteriophages; Cross Reactions; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Female; Gastrointestinal Hormones; Immunization; Mice; Mice, Inbred BALB C; Natriuretic Peptides; Toxoids; Vaccines, Subunit; Vaccines, Virus-Like Particle

Infection with enterotoxigenic

Topics: Animals; Antibodies, Bacterial; Antibodies, Neutralizing; Bacterial Toxins; Cross Reactions; Enterotoxigenic Escherichia coli; Enterotoxins; Escherichia coli Infections; Escherichia coli Proteins; Escherichia coli Vaccines; Gastrointestinal Hormones; Humans; Immunization; Mice; Mice, Inbred BALB C; Natriuretic Peptides; Swine

Heat-stable toxin (STa)-producing enterotoxigenic

Topics: Animals; Antibodies, Bacterial; Antibodies, Neutralizing; Antigens, Bacterial; Bacterial Toxins; Child; Cross Reactions; Enterotoxigenic Escherichia coli; Enterotoxins; Escherichia coli Infections; Female; Gastrointestinal Hormones; Hot Temperature; Humans; Immunization; Mice; Mutation; Natriuretic Peptides; Toxoids