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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kisiela, Dagmara I. Tchesnokova, Veronika Liu, Yan Avagyan, Hovhannes Sokurenko, Evgeni V. Thomas, Wendy E. Wu, Xue-ru Aprikian, Pavel Rodriguez, Victoria B. |
| Description | Author Affiliation: Kisiela DI ( Departments of Microbiology and Bioengineering, University of Washington, Seattle, WA 98195.); |
| Abstract | Inhibiting antibodies targeting receptor-binding pockets in proteins is a major focus in the development of vaccines and in antibody-based therapeutic strategies. Here, by using a common mannose-specific fimbrial adhesin of Escherichia coli, FimH, we demonstrate that locking the adhesin in a low-binding conformation induces the production of binding pocket-specific, adhesion-inhibiting antibodies. A di-sulfide bridge was introduced into the conformationally dynamic FimH lectin domain, away from the mannose-binding pocket but rendering it defective with regard to mannose binding. Unlike the native, functionally active lectin domain, the functionally defective domain was potent in inducing inhibitory monoclonal antibodies that blocked FimH-mediated bacterial adhesion to epithelial cells and urinary bladder infection in mice. Inhibition of adhesion involved direct competition between the antibodies and mannose for the binding pocket. Binding pocket-specific inhibitory antibodies also were abundant in polyclonal immune serum raised against the functionally defective lectin domain. The monoclonal antibodies elicited against the binding-defective protein bound to the high-affinity conformation of the adhesin more avidly than to the low-affinity form. However, both soluble mannose and blood plasma more strongly inhibited antibody recognition of the high-affinity FimH conformation than the low-affinity form. We propose that in the functionally active conformation the binding-pocket epitopes are shielded from targeted antibody development by ligand masking and that strong immunogenicity of the binding pocket is unblocked when the adhesive domain is in the nonbinding conformation. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 47 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-11-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adhesins, Escherichia Coli Chemistry Antibodies, Monoclonal Immunology Binding Sites, Antibody Escherichia Coli Metabolism Fimbriae Proteins Models, Molecular Protein Conformation Urinary Bladder Diseases Microbiology Genetics Animals Bacterial Adhesion Mannose Mice Mutation, Missense Protein Binding Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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