Nasally administered cholera toxin A-subunit acts as a mucosal adjuvant

Campos, Emilio A.; Namikoshi, Jun; Maeba, Satomi; Yamamoto, Masafumi; Fukumoto, Masahiko; Yamamoto, Hirotsugu

doi:10.2334/josnusd.45.25

Cited by 4 publications

(2 citation statements)

References 29 publications

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“…Here we used the adjuvant cholera toxin, which is highly efficient on mucosal surfaces in mice. However, it has not yet been studied extensively in humans, and the toxic potential remains unclear (9). In contrast to previous observations, we found in our study that coadministration of CT and protein antigens without previous cross-linking provided potent stimulation of immune responses (1).…”

Section: Discussioncontrasting

confidence: 56%

A Multiepitope Subunit Vaccine Conveys Protection against Extraintestinal PathogenicEscherichia coliin Mice

et al. 2010

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Infections due to extraintestinal pathogenic Escherichia coli (ExPEC) are common in humans and animals and include urinary tract infections (from uropathogenic E. coli [UPEC]), septicemia, and wound infections. These infections result in significant morbidity and mortality and in high health care costs. In view of the increasing number of ExPEC infections and the ever-growing antibiotic resistance capability of ExPEC isolates, preventive measures such as an effective vaccine against ExPEC are desirable. An ExPEC vaccine may be cost-effective for select patient groups. Previous vaccine candidates consisted of single target proteins or whole ExPEC cells. Here we describe a subunit vaccine against ExPEC which is based on immunodominant epitopes of the virulence-associated ExPEC proteins FyuA, IroN, ChuA, IreA, Iha, and Usp. Using a novel approach of computer-aided design, two completely artificial genes were created, both encoding eight peptide domains derived from these ExPEC proteins. The recombinant expression of these two genes resulted in a protein vaccine directed against ExPEC but not against commensal E. coli of the gut flora. In mice, the vaccine was highly immunogenic, eliciting both strong humoral and cellular immune responses. Nasal application resulted in high secretory immunoglobulin A (sIgA) production, which was detectable on the mucosal surface of the urogenital tract. Finally, it conveyed protection, as shown by a significant reduction of bacterial load in a mouse model of ExPEC peritonitis. This study provides evidence that a novel vaccine design encompassing distinct epitopes of virulenceassociated ExPEC proteins may represent a means for providing a protective and pathogen-specific vaccine.

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Section: Discussioncontrasting

confidence: 56%

A Multiepitope Subunit Vaccine Conveys Protection against Extraintestinal PathogenicEscherichia coliin Mice

et al. 2010

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“…Also, given that TCTA1T lacks CTB domain, our finding indicates that CTB domain may be dispensable for the adjuvanticity of CT. This notion is also supported by the previous finding that CTA domain determines the adjuvanticity of CT [ 38 ].…”

Section: Discussionsupporting

confidence: 79%

Development of Safe and Non-Self-Immunogenic Mucosal Adjuvant by Recombinant Fusion of Cholera Toxin A1 Subunit with Protein Transduction Domain

Shim

Cheon

Lee

et al. 2018

Journal of Immunology Research

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Potential use of cholera toxin (CT) as a mucosal vaccine adjuvant has been documented in a variety of animal models. However, native CT is highly toxic to be used as a mucosal adjuvant in humans. Here, we demonstrate a new approach to generate a mucosal adjuvant by replacing the B subunit of CT with HIV-1 Tat protein transduction domain (PTD), which efficiently delivers fusion proteins into the cell cytoplasm by unspecific binding to cell surface. We compared the adjuvanticity and toxicity of Tat PTD-CTA1-Tat PTD (TCTA1T) with those of CT. Our results indicate that intranasal (i.n.) delivery of ovalbumin (OVA) with TCTA1T significantly augments the OVA-specific systemic and mucosal antibody responses to levels comparable to those seen with CT adjuvant. Moreover, in vivo cytotoxic T lymphocyte activity elicited by TCTA1T was significantly higher than that elicited by a mutant TCTA1T (TmCTA1T) lacking ADP-ribosyltransferase function. In addition, coadministration of influenza M2 protein with TCTA1T conferred near complete protection against lethal influenza virus challenge. Importantly, TCTA1T, in contrast to CT, did not induce serum IgG antibody responses to itself and was shown to be nontoxic. These results suggest that TCTA1T may be a safe and effective adjuvant when given by mucosal routes.

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Heat-Labile Enterotoxins

Jobling

Holmes

2006

EcoSal Plus

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Heat-labile enterotoxins (LTs) of Escherichia coli are closely related to cholera toxin (CT), which was originally discovered in 1959 in culture filtrates of the gram-negative bacterium Vibrio cholerae. Several other gram-negative bacteria also produce enterotoxins related to CT and LTs, and together these toxins form the V. cholerae-E. coli family of LTs. Strains of E. coli causing a cholera-like disease were designated enterotoxigenic E. coli (ETEC) strains. The majority of LTI genes (elt) are located on large, self-transmissible or mobilizable plasmids, although there are instances of LTI genes being located on chromosomes or carried by a lysogenic phage. The stoichiometry of A and B subunits in holotoxin requires the production of five B monomers for every A subunit. One proposed mechanism is a more efficient ribosome binding site for the B gene than for the A gene, increasing the rate of initiation of translation of the B gene independently from A gene translation. The three-dimensional crystal structures of representative members of the LT family (CT, LTpI, and LTIIb) have all been determined by X-ray crystallography and found to be highly similar. Site-directed mutagenesis has identified many residues in the CT and LT A subunits, including His44, Val53, Ser63, Val97, Glu110, and Glu112, that are critical for the structures and enzymatic activities of these enterotoxins. For the enzymatically active A1 fragment to reach its substrate, receptor-bound holotoxin must gain access to the cytosol of target cells.

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Nasally administered cholera toxin A-subunit acts as a mucosal adjuvant

Cited by 4 publications

References 29 publications

A Multiepitope Subunit Vaccine Conveys Protection against Extraintestinal PathogenicEscherichia coliin Mice

A Multiepitope Subunit Vaccine Conveys Protection against Extraintestinal PathogenicEscherichia coliin Mice

Development of Safe and Non-Self-Immunogenic Mucosal Adjuvant by Recombinant Fusion of Cholera Toxin A1 Subunit with Protein Transduction Domain

Heat-Labile Enterotoxins

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