scholarly journals Zonula Occludens Toxin Acts as an Adjuvant through Different Mucosal Routes and Induces Protective Immune Responses

2003 ◽  
Vol 71 (4) ◽  
pp. 1897-1902 ◽  
Author(s):  
Mariarosaria Marinaro ◽  
Alessio Fasano ◽  
Maria Teresa De Magistris
Keyword(s):  
Immune Responses ◽  
Tight Junctions ◽  
Mucosal Permeability ◽  
Mucosal Adjuvant ◽  
Promising Tool ◽  
Zonula Occludens ◽  
Specific Serum ◽  
Mucosal Vaccines ◽  
Zonula Occludens Toxin ◽  
Putative Binding Site

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.

scholarly journals Zonula Occludens Toxin Is a Powerful Mucosal Adjuvant for Intranasally Delivered Antigens

1999 ◽  
Vol 67 (3) ◽  
pp. 1287-1291 ◽  
Author(s):  
Mariarosaria Marinaro ◽  
Annalisa di Tommaso ◽  
Sergio Uzzau ◽  
Alessio Fasano ◽  
Maria Teresa de Magistris
Keyword(s):  
Immune Responses ◽  
Mucosal Barrier ◽  
Intestinal Epithelial ◽  
Adjuvant Activity ◽  
Mucosal Adjuvant ◽  
Zonula Occludens ◽  
Hexahistidine Tag ◽  
Specific Igg ◽  
Toxigenic Strains ◽  
Zonula Occludens Toxin

ABSTRACT Zonula occludens toxin (Zot) is produced by toxigenic strains ofVibrio cholerae and has the ability to reversibly alter intestinal epithelial tight junctions, allowing the passage of macromolecules through the mucosal barrier. In the present study, we investigated whether Zot could be exploited to deliver soluble antigens through the nasal mucosa for the induction of antigen-specific systemic and mucosal immune responses. Intranasal immunization of mice with ovalbumin (Ova) and recombinant Zot, either fused to the maltose-binding protein (MBP-Zot) or with a hexahistidine tag (His-Zot), induced anti-Ova serum immunoglobulin G (IgG) titers that were approximately 40-fold higher than those induced by immunization with antigen alone. Interestingly, Zot also stimulated high anti-Ova IgA titers in serum, as well as in vaginal and intestinal secretions. A comparison with Escherichia coli heat-labile enterotoxin (LT) revealed that the adjuvant activity of Zot was only sevenfold lower than that of LT. Moreover, Zot and LT induced similar patterns of Ova-specific IgG subclasses. The subtypes IgG1, IgG2a, and IgG2b were all stimulated, with a predominance of IgG1 and IgG2b. In conclusion, our results highlight Zot as a novel potent mucosal adjuvant of microbial origin.

Human zonulin, a potential modulator of intestinal tight junctions

2000 ◽  
Vol 113 (24) ◽  
pp. 4435-4440 ◽  
Author(s):  
W. Wang ◽  
S. Uzzau ◽  
S.E. Goldblum ◽  
A. Fasano
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Ussing Chamber ◽  
Intestinal Lumen ◽  
Epithelial Surface ◽  
Ussing Chambers ◽  
Zonula Occludens ◽  
Surface Receptor ◽  
Dynamic Structures ◽  
Zonula Occludens Toxin

Intercellular tight junctions are dynamic structures involved in vectorial transport of water and electrolytes across the intestinal epithelium. Zonula occludens toxin derived from Vibrio cholerae interacts with a specific intestinal epithelial surface receptor, with subsequent activation of a complex intracellular cascade of events that regulate tight junction permeability. We postulated that this toxin may mimic the effect of a functionally and immunologically related endogenous modulator of intestinal tight junctions. Affinity-purified anti-zonula occludens toxin antibodies and the Ussing chamber assay were used to screen for one or more mammalian zonula occludens toxin analogues in both fetal and adult human intestine. A novel protein, zonulin, was identified that induces tight junction disassembly in non-human primate intestinal epithelia mounted in Ussing chambers. Comparison of amino acids in the active zonula occludens toxin fragment and zonulin permitted the identification of the putative receptor binding domain within the N-terminal region of the two proteins. Zonulin likely plays a pivotal role in tight junction regulation during developmental, physiological, and pathological processes, including tissue morphogenesis, movement of fluid, macromolecules and leukocytes between the intestinal lumen and the interstitium, and inflammatory/autoimmune disorders.

Dissociation of ZO1-occludin complex is involved in zonula occludens toxin (Zot)-mediated disassembly of intestinal tight junctions

2001 ◽  
Vol 120 (5) ◽  
pp. A699
Author(s):  
Tammara L. Watts ◽  
Timothy D. Kiser ◽  
Regina A. Macatangay ◽  
Simeon E. Goldblum ◽  
Alessio Fasano
Keyword(s):  
Tight Junctions ◽  
Zonula Occludens ◽  
Zonula Occludens Toxin

Mucosal and systemic immune responses of mice to tetanus toxoid coadministered nasally with AFCo1

2011 ◽  
Vol 57 (3) ◽  
pp. 256-261 ◽  
Author(s):  
Belkis Romeu ◽  
Elyzabeth González ◽  
Judith del Campo ◽  
Reynaldo Acevedo ◽  
Caridad Zayas ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tetanus Toxoid ◽  
Mucosal Vaccine ◽  
Vaccine Adjuvants ◽  
Mucosal Adjuvant ◽  
Mucosal Vaccines ◽  
Nasal Immunization ◽  
Human Use ◽  
Vaginal Wash ◽  
Systemic Compartment

Mucosal immune responses are an early and important line of defense against pathogens. The current understanding of the mucosal immune system allows us to consider the use of nasal immunization for induction of antigen-specific immune responses at the mucosal surface and the systemic compartment. Mucosal adjuvants are key for developing novel mucosal vaccines and represent 1 approach to improving mucosal and systemic immunity. However, few mucosal vaccine adjuvants are currently approved for human use. Neisseria meningitidis B proteoliposome-derived cochleate (AFCo1 — Adjuvant Finlay Cochleate 1) has been demonstrated to be a potent mucosal adjuvant. The present work demonstrates that intranasal immunization of 3 doses of tetanus toxoid (TT) coadministered with AFCo1 in mice promotes high systemic and mucosal responses. The anti-TT IgG serum titers and the mucosal anti-TT IgA in saliva and vaginal wash were significantly higher than TT alone. The analysis of antibody subclasses showed that intranasal administration of AFCo1 + TT induced not only IgG1 but also IgG2a anti-TT antibodies at levels comparable to those obtained with TT vaccine (vax-TET). These data support the fact that AFCo1 is a potent mucosal adjuvant in nasal immunization to a coadministered protein antigen.

scholarly journals Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro.

1995 ◽  
Vol 96 (2) ◽  
pp. 710-720 ◽  
Author(s):  
A Fasano ◽  
C Fiorentini ◽  
G Donelli ◽  
S Uzzau ◽  
J B Kaper ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tight Junctions ◽  
Actin Reorganization ◽  
Kinase C ◽  
Zonula Occludens ◽  
Zonula Occludens Toxin

Dissociation of ZO1-occludin complex is involved in zonula occludens toxin (Zot)-mediated disassembly of intestinal tight junctions

2001 ◽  
Vol 120 (5) ◽  
pp. A699-A699
Author(s):  
T WATTS ◽  
T KISER ◽  
R MACATANGAY ◽  
S GOLDBLUM ◽  
A FASANO
Keyword(s):  
Tight Junctions ◽  
Zonula Occludens ◽  
Zonula Occludens Toxin

scholarly journals An Intranasally Delivered Toll-Like Receptor 7 Agonist Elicits Robust Systemic and Mucosal Responses to Norwalk Virus-Like Particles

2010 ◽  
Vol 17 (12) ◽  
pp. 1850-1858 ◽  
Author(s):  
Lissette S. Velasquez ◽  
Brooke E. Hjelm ◽  
Charles J. Arntzen ◽  
Melissa M. Herbst-Kralovetz
Keyword(s):  
Immune Responses ◽  
Immune Protection ◽  
Norwalk Virus ◽  
Toll Like Receptor ◽  
Adjuvant Activity ◽  
Mucosal Adjuvant ◽  
Virus Like Particles ◽  
Vaccine Trials ◽  
Specific Serum ◽  
Tlr7 Agonist

ABSTRACT Norwalk virus (NV) is an enteric pathogen from the genus Norovirus and a major cause of nonbacterial gastroenteritis in humans. NV virus-like particles (VLPs) are known to elicit systemic and mucosal immune responses when delivered nasally; however, the correlates of immune protection are unknown, and codelivery with a safe and immunogenic mucosal adjuvant may enhance protective anti-NV immune responses. Resiquimod (R848), an imidazoquinoline-based Toll-like receptor 7 and/or 8 (TLR7/8) agonist, is being evaluated as an adjuvant in FDA-approved clinical vaccine trials. As such, we evaluated the adjuvant activity of two imidazoquinoline-based TLR7 and TLR7/8 agonists when codelivered intranasally with plant-derived NV VLPs. We also compared the activity of these agonists to the gold standard mucosal adjuvant, cholera toxin (CT). Our results indicate that codelivery with the TLR7 agonist, gardiquimod (GARD), induces NV VLP-specific serum IgG and IgG isotype responses and mucosal IgA responses in the gastrointestinal, respiratory, and reproductive tracts that are superior to those induced by R848 and comparable to those induced by the mucosal adjuvant CT. This study supports the continued investigation of GARD as a mucosal adjuvant for NV VLPs and possible use for other VLP-based vaccines for which immune responses at distal mucosal sites (e.g., respiratory and reproductive tracts) are desired.

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