| Summary: | The pathogenic bacterium <i>Shigella</i> is a leading cause of diarrheal disease and mortality, disproportionately affecting young children in low-income countries. The increasing prevalence of antibiotic resistance in <i>Shigella</i> necessitates an effective vaccine, for which the bacterial lipopolysaccharide O-antigen is the primary target. <i>S. flexneri</i> serotype 6 has been proposed as a multivalent vaccine component to ensure broad protection against <i>Shigella</i>. We have previously explored the conformations of <i>S. flexneri</i> O-antigens from serogroups Y, 2, 3, and 5 that share a common saccharide backbone (serotype Y). Here we consider serogroup 6, which is of particular interest because of an altered backbone repeat unit with non-stoichiometric O-acetylation, the antigenic and immunogenic importance of which have yet to be established. Our simulations show significant conformational changes in serogroup 6 relative to the serotype Y backbone. We further find that O-acetylation has little effect on conformation and hence may not be essential for the antigenicity of serotype 6. This is corroborated by an in vivo study in mice, using Generalized Modules for Membrane Antigens (GMMA) as O-antigen delivery systems, that shows that O-acetylation does not have an impact on the immune response elicited by the <i>S. flexneri</i> serotype 6 O-antigen.
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