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• W2085207619 endingPage "3591" @default.
• W2085207619 startingPage "3576" @default.
• W2085207619 abstract "The adenylate cyclase toxin (ACT) is a multifunctional virulence factor secreted by Bordetella species. Upon interaction of its C-terminal hemolysin moiety with the cell surface receptor αMβ2 integrin, the N-terminal cyclase domain translocates into the host cell cytosol where it rapidly generates supraphysiological cAMP concentrations, which inhibit host cell anti-bacterial activities. Although ACT has been shown to induce protective immunity in mice, it is not included in any current acellular pertussis vaccines due to protein stability issues and a poor understanding of its role as a protective antigen. Here, we aimed to determine whether any single domain could recapitulate the antibody responses induced by the holo-toxin and to characterize the dominant neutralizing antibody response. We first immunized mice with ACT and screened antibody phage display libraries for binding to purified ACT. The vast majority of unique antibodies identified bound the C-terminal repeat-in-toxin (RTX) domain. Representative antibodies binding two nonoverlapping, neutralizing epitopes in the RTX domain prevented ACT association with J774A.1 macrophages and soluble αMβ2 integrin, suggesting that these antibodies inhibit the ACT-receptor interaction. Sera from mice immunized with the RTX domain showed similar neutralizing activity as ACT-immunized mice, indicating that this domain induced an antibody response similar to that induced by ACT. These data demonstrate that RTX can elicit neutralizing antibodies and suggest it may present an alternative to ACT.Background: The protective antigen adenylate cyclase toxin (ACT) has not been included in current pertussis vaccines partly due to incomplete understanding of its protective epitopes.Results: The repeat-in-toxin (RTX) domain is immunodominant in mice and contains neutralizing epitopes.Conclusion: The RTX domain induces similar neutralizing antibody responses as ACT.Significance: The RTX domain may be an alternative to ACT for inclusion in future vaccines. The adenylate cyclase toxin (ACT) is a multifunctional virulence factor secreted by Bordetella species. Upon interaction of its C-terminal hemolysin moiety with the cell surface receptor αMβ2 integrin, the N-terminal cyclase domain translocates into the host cell cytosol where it rapidly generates supraphysiological cAMP concentrations, which inhibit host cell anti-bacterial activities. Although ACT has been shown to induce protective immunity in mice, it is not included in any current acellular pertussis vaccines due to protein stability issues and a poor understanding of its role as a protective antigen. Here, we aimed to determine whether any single domain could recapitulate the antibody responses induced by the holo-toxin and to characterize the dominant neutralizing antibody response. We first immunized mice with ACT and screened antibody phage display libraries for binding to purified ACT. The vast majority of unique antibodies identified bound the C-terminal repeat-in-toxin (RTX) domain. Representative antibodies binding two nonoverlapping, neutralizing epitopes in the RTX domain prevented ACT association with J774A.1 macrophages and soluble αMβ2 integrin, suggesting that these antibodies inhibit the ACT-receptor interaction. Sera from mice immunized with the RTX domain showed similar neutralizing activity as ACT-immunized mice, indicating that this domain induced an antibody response similar to that induced by ACT. These data demonstrate that RTX can elicit neutralizing antibodies and suggest it may present an alternative to ACT. Background: The protective antigen adenylate cyclase toxin (ACT) has not been included in current pertussis vaccines partly due to incomplete understanding of its protective epitopes. Results: The repeat-in-toxin (RTX) domain is immunodominant in mice and contains neutralizing epitopes. Conclusion: The RTX domain induces similar neutralizing antibody responses as ACT. Significance: The RTX domain may be an alternative to ACT for inclusion in future vaccines. The Bordetella adenylate cyclase repeat-in-toxin (RTX) domain is immunodominant and elicits neutralizing antibodies.Journal of Biological ChemistryVol. 290Issue 38PreviewVOLUME 290 (2015) PAGES 3576–3591 Full-Text PDF Open Access" @default.
• W2085207619 created "2016-06-24" @default.
• W2085207619 creator A5013803583 @default.
• W2085207619 creator A5046526368 @default.
• W2085207619 date "2015-02-01" @default.
• W2085207619 modified "2023-09-29" @default.
• W2085207619 title "The Bordetella Adenylate Cyclase Repeat-in-Toxin (RTX) Domain Is Immunodominant and Elicits Neutralizing Antibodies" @default.
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• W2085207619 doi "https://doi.org/10.1074/jbc.m114.585281" @default.
• W2085207619 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4645631" @default.
• W2085207619 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26386047" @default.
• W2085207619 hasPublicationYear "2015" @default.
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