Kintz E, Heiss C, Black I, Donohue N, Brown N, Davies MR, Azadi P, Baker S, Kaye PM, van der Woude M
Salmonella Typhi is a human restricted Gram-negative bacterial pathogen, responsible for causing an estimated 27 million cases of typhoid fever annually leading to 217,000 deaths, and current vaccines do not offer full protection. The O-antigen side chain of the lipopolysaccharide is an immunodominant antigen, can define host-pathogen interactions, and is under consideration as a vaccine target for some Gram-negative species. The composition of the O-antigen can be modified by activity of glycosyltransferase (gtr) operons acquired by horizontal gene transfer. Here we investigate the role of two gtr operons we identified in the S. Typhi genome. Strains were engineered to express specific gtr operons. Full chemical analysis of the O-antigen of these strains identified gtr-dependent glucosylation and acetylation. The glucosylated form of the O-antigen mediated enhanced survival in human serum and decreased complement binding. A single nucleotide deviation from an epigenetic phase variation signature sequence rendered expression of this glucosylating gtr operon uniform in the population. In contrast, expression of the acetylating gtrC is controlled by epigenetic phase variation. Acetylation did not affect serum survival, but phase variation can be an immune evasion mechanism and thus this modification may contribute to persistence in a host. In murine immunization studies, both O-antigen modifications were generally immunodominant. Our results emphasize that natural O-antigen modification should be taken into consideration when assessing responses to vaccines, especially O-antigen based vaccines, and that the Salmonella gtr repertoire may confound the protective efficacy of broad ranging Salmonella lipopolysaccharide conjugate vaccines.
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