Glycoconjugate vaccines are composed of microbial poly- or oligosaccharides covalently linked to a carrier protein. In the absence of structural information, long poly- or oligosaccharides... Show moreGlycoconjugate vaccines are composed of microbial poly- or oligosaccharides covalently linked to a carrier protein. In the absence of structural information, long poly- or oligosaccharides extracted from bacteria are employed to cover all relevant glyco epitopes and elicit an effective immune response. The comprehension of the structural basis for the immune recognition of carbohydrate antigens and the elucidation of minimal epitopes is key to understand their mechanism of action and support the rational design of modern glycoconjugate vaccines.Group B streptococcus (GBS) is a Gram-positive bacterium, cause of infections in pregnant women and newborns, whose capsular polysaccharide (CPS) is a major virulence factor.A small library of GBS glycans from serotypes Ia, Ib and III CPSs was synthesized. These oligosaccharides were used to model the conformational preferences of the corresponding CPS and to characterize the interactions to protective anti PS monoclonal antibodies. Conjugation to carrier proteins of the most promising fragments and evaluation in vivo of the obtained glycoconjugates showed that a hexasaccharide corresponding to the minimal structural epitope of GBS III was able to elicit anti PSIII functional IgGs. Overall, the findings described in this Thesis open the path to the design of GBS vaccines based on synthetic oligosaccharides. Show less
A prominent feature of severe streptococcal infections is the profound inflammatory response that contributes to systemic toxicity. In sepsis the dysregulated host response involves both... Show moreA prominent feature of severe streptococcal infections is the profound inflammatory response that contributes to systemic toxicity. In sepsis the dysregulated host response involves both immunological and nonimmunological pathways. Here, we report a fatal case of an immunocompetent healthy female presenting with toxic shock and purpura fulminans caused by group B streptococcus (GBS; serotype III, CC19). The strain (LUMC16) was pigmented and hyperhemolytic. Stimulation of human primary cells with hyperhemolytic LUMC16 and STSS/NF-HH strains and pigment toxin resulted in a release of proinflammatory mediators, including tumor necrosis factor, interleukin (IL)-1 beta, and IL-6. In addition, LUMC16 induced blood clotting and showed factor XII activity on its surface, which was linked to the presence of the pigment. The expression of pigment was not linked to a mutation within the CovR/S region. In conclusion, our study shows that the hemolytic lipid toxin contributes to the ability of GBS to cause systemic hyperinflammation and interferes with the coagulation system. Show less
