title: Zonula occludens toxin acts as an adjuvant through different mucosal routes and induces protective immune responses.
abstract: Zonula occludens toxin (Zot) is produced by Vibrio cholerae and has the ability to increase mucosal permeability by reversibly affecting the structure of tight junctions. Because of this property, Zot is a promising tool for mucosal drug and antigen (Ag) delivery. Here we show that Zot acts as a mucosal adjuvant to induce long-lasting and protective immune responses upon mucosal immunization of mice. Indeed, the intranasal delivery of ovalbumin with two different recombinant forms of Zot in BALB/c mice resulted in high Ag-specific serum immunoglobulin G titers that were maintained over the course of a year. Moreover, His-Zot induced humoral and cell-mediated responses to tetanus toxoid in C57BL/6 mice and protected the mice against a systemic challenge with tetanus toxin. In addition, we found that Zot also acts as an adjuvant through the intrarectal route and that it has very low immunogenicity compared to the adjuvant Escherichia coli heat-labile enterotoxin. Finally, by using an octapeptide representing the putative binding site of Zot and of its endogenous analogue zonulin, we provide evidence that Zot may bind a mucosal receptor on nasal mucosa and may mimic an endogenous regulator of tight junctions to deliver Ags in the submucosa. In conclusion, Zot is a novel and effective mucosal adjuvant that may be useful for the development of mucosal vaccines.
authors.affiliation: Laboratory of Bacteriology and Medical Mycology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Marinaro
authors.forename: Alessio
authors.initials: A
authors.lastname: Fasano
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: De Magistris
mesh_terms: D000276:Adjuvants, Immunologic; D000281:Administration, Intranasal; D000285:Administration, Rectal; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood*; D002772:Cholera Toxin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D003017:Clostridium tetani / Q000378:metabolism / Q000472:pathogenicity; D004731:Endotoxins; D005260:Female; D018928:Immunity, Mucosal; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D013742:Tetanus / Q000517:prevention & control; D013744:Tetanus Toxin / Q000633:toxicity; D013745:Tetanus Toxoid / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D004731:Endotoxins; D011994:Recombinant Proteins; D013744:Tetanus Toxin; D013745:Tetanus Toxoid; C077728:zonula occludens toxin, Vibrio cholerae; D010047:Ovalbumin; D002772:Cholera Toxin