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Lu Z, Rynkiewicz MJ, Yang CY, Madico G, Perkins HM, Roche MI, Seaton BA, Sharon J
Functional and Structural Characterization of Francisella tularensis O-Antigen Antibodies at the Low End of Antigen Reactivity
Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 33(4) (2014)
235-245
|
-4)-a-D-GalpNAcA6NH2-(1-4)-a-D-GalpNAcA6NH2-(1-3)-b-D-QuipNAc-(1-2)-b-D-Quip4NFo-(1- |
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Francisella tularensis
(NCBI TaxID 263,
species name lookup)
Francisella tularensis ssp. holarctica LVS
(NCBI TaxID 376619,
species name lookup)
Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Associated disease: respiratory tularemia [ICD11:
1B94 
, ICD11:
XN0BX ];
infection due to Francisella tularensis [ICD11:
XN0BX ]
NCBI PubMed ID: 25171003Publication DOI: 10.1089/mab.2014.0022Journal NLM ID: 101590955Publisher: New Rochelle, NY: Mary Ann Liebert, Inc.
Correspondence: jsharon
bu.edu
Institutions: Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, Massachusetts
The O-antigen (OAg) of the Gram-negative bacterium Francisella tularensis (Ft), which is both a capsular polysaccharide and a component of lipopolysaccharide, is comprised of tetrasaccharide repeats and induces antibodies mainly against repeating internal epitopes. We previously reported on several BALB/c mouse monoclonal antibodies (MAbs) that bind to internal Ft OAg epitopes and are protective in mouse models of respiratory tularemia. We now characterize three new internal Ft OAg IgG2a MAbs, N203, N77, and N24, with 10- to 100-fold lower binding potency than previously characterized internal-OAg IgG2a MAbs, despite sharing one or more variable region germline genes with some of them. In a mouse model of respiratory tularemia with the highly virulent Ft type A strain SchuS4, the three new MAbs reduced blood bacterial burden with potencies that mirror their antigen-binding strength; the best binder of the new MAbs, N203, prolonged survival in a dose-dependent manner, but was at least 10-fold less potent than the best previously characterized IgG2a MAb, Ab52. X-ray crystallographic studies of N203 Fab showed a flexible binding site in the form of a partitioned groove, which cannot provide as many contacts to OAg as does the Ab52 binding site. These results reveal structural features of antibodies at the low end of reactivity with multi-repeat microbial carbohydrates and demonstrate that such antibodies still have substantial protective effects against infection.
antibodies, monoclonal antibodies, capsular polysaccharide, Gram-negative bacteria, tularemia, BALB/c mouse, epitopeFrancisella tularensis
Structure type: polymer chemical repeating unit
Location inside paper: p.235
Compound class: CPS, O-polysaccharide, O-antigen
Contained glycoepitopes: IEDB_151083,IEDB_221847,IEDB_221848
Methods: X-ray, ELISA, Western blotting, biological assays, RT-PCR, binding assays
Biological activity: analysis of the antigen binding site
Comments, role: published polymerization frame was shifted for conformity with other records.
3D data: 3D data
Related record ID(s): 30412
NCBI Taxonomy refs (TaxIDs): 263,
376619Reference(s) to other database(s): GTC:G66306WB, GlycomeDB:
3488
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There is only one chemically distinct structure:
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Lu Z, Rynkiewicz MJ, Yang CY, Madico G, Perkins HM, Roche MI, Seaton BA, Sharon J
Functional and Structural Characterization of Francisella tularensis O-Antigen Antibodies at the Low End of Antigen Reactivity
Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 33(4) (2014)
235-245
|
a-D-GalpNAcA6NH2-(1-4)-a-D-GalpNAcA6NH2-(1-3)-b-D-QuipNAc-(1-2)-b-D-Quip4NFo-(1-4)-a-D-GalpNAcA6NH2-(1-4)-a-D-GalpNAcA6NH2 |
Show graphically |
Francisella tularensis
(NCBI TaxID 263,
species name lookup)
Francisella tularensis ssp. holarctica LVS
(NCBI TaxID 376619,
species name lookup)
Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Associated disease: respiratory tularemia [ICD11:
1B94 , ICD11:
XN0BX ];
infection due to Francisella tularensis [ICD11:
XN0BX ]
NCBI PubMed ID: 25171003Publication DOI: 10.1089/mab.2014.0022Journal NLM ID: 101590955Publisher: New Rochelle, NY: Mary Ann Liebert, Inc.
Correspondence: jsharon
bu.edu
Institutions: Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, Massachusetts
The O-antigen (OAg) of the Gram-negative bacterium Francisella tularensis (Ft), which is both a capsular polysaccharide and a component of lipopolysaccharide, is comprised of tetrasaccharide repeats and induces antibodies mainly against repeating internal epitopes. We previously reported on several BALB/c mouse monoclonal antibodies (MAbs) that bind to internal Ft OAg epitopes and are protective in mouse models of respiratory tularemia. We now characterize three new internal Ft OAg IgG2a MAbs, N203, N77, and N24, with 10- to 100-fold lower binding potency than previously characterized internal-OAg IgG2a MAbs, despite sharing one or more variable region germline genes with some of them. In a mouse model of respiratory tularemia with the highly virulent Ft type A strain SchuS4, the three new MAbs reduced blood bacterial burden with potencies that mirror their antigen-binding strength; the best binder of the new MAbs, N203, prolonged survival in a dose-dependent manner, but was at least 10-fold less potent than the best previously characterized IgG2a MAb, Ab52. X-ray crystallographic studies of N203 Fab showed a flexible binding site in the form of a partitioned groove, which cannot provide as many contacts to OAg as does the Ab52 binding site. These results reveal structural features of antibodies at the low end of reactivity with multi-repeat microbial carbohydrates and demonstrate that such antibodies still have substantial protective effects against infection.
antibodies, monoclonal antibodies, capsular polysaccharide, Gram-negative bacteria, tularemia, BALB/c mouse, epitopeFrancisella tularensis
Structure type: oligomer
Location inside paper: p.236
Trivial name: epitope of the OAg, V-shaped epitope
Compound class: O-polysaccharide, O-antigen
Methods: X-ray, ELISA, Western blotting, biological assays, RT-PCR, binding assays
Biological activity: analysis of the antigen binding site
3D data: 3D data
Related record ID(s): 30096
NCBI Taxonomy refs (TaxIDs): 263,
376619Reference(s) to other database(s): GTC:G59392BO
Show glycosyltransferases
There is only one chemically distinct structure:
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