Abstract
Lipopolysaccharide (LPS) O-antigen (O-Ag) is known to limit antibody binding to surface antigens, although the relationship between antibody, O-Ag and other outer-membrane antigens is poorly understood. Here we report, immunization with the trimeric porin OmpD from Salmonella Typhimurium (STmOmpD) protects against infection. Atomistic molecular dynamics simulations indicate this is because OmpD trimers generate footprints within the O-Ag layer sufficiently sized for a single IgG Fab to access. While STmOmpD differs from its orthologue in S. Enteritidis (SEn) by a single amino-acid residue, immunization with STmOmpD confers minimal protection to SEn. This is due to the OmpD-O-Ag interplay restricting IgG binding, with the pairing of OmpD with its native O-Ag being essential for optimal protection after immunization. Thus, both the chemical and physical structure of O-Ag are key for the presentation of specific epitopes within proteinaceous surface-antigens. This enhances combinatorial antigenic diversity in Gram-negative bacteria, while reducing associated fitness costs.
Highlights
Lipopolysaccharide (LPS) O-antigen (O-Ag) is known to limit antibody binding to surface antigens, the relationship between antibody, O-Ag and other outer-membrane antigens is poorly understood
The induced anti-STmOmpD IgG bound to the surface of two different isolates of Salmonella Typhimurium (STm): the model laboratory strain SL1344 and a representative invasive African isolate of STm, D23580, which was originally isolated from an African patient[13] (Fig. 1a)
We assessed if anti-STmOmpD sera could kill bacteria in a well-established serum bactericidal assay (SBA), which uses human sera depleted of anti-STm antibodies, as a source of complement[14]
Summary
Lipopolysaccharide (LPS) O-antigen (O-Ag) is known to limit antibody binding to surface antigens, the relationship between antibody, O-Ag and other outer-membrane antigens is poorly understood. This is due to the OmpD-O-Ag interplay restricting IgG binding, with the pairing of OmpD with its native O-Ag being essential for optimal protection after immunization Both the chemical and physical structure of OAg are key for the presentation of specific epitopes within proteinaceous surface-antigens. Even more antigenically complex are vaccines based on attenuated organisms, which offer the greatest breadth of antigen inclusion, but with little empirical rationalization as to which antigens are protective This highlights our limited understanding of how protective antibodies interact with the bacterial surface. OmpA is a monomeric protein that is a common target of antibody after infection in mice and humans, and OmpD is found in the cell envelope in trimeric form[9] Both antigens are highly conserved across Gram-negative bacteria, within the same genus, meaning that an antibody to such a protein from one serovar may cross-protect against another. Our findings suggest that how small changes in proteinaceous surface antigens of Gram-negative bacteria can combine with O-Ag to maximize antigen diversity within a single species, and have implications for generating vaccines offering multi-serovar protection
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