Sialic Acid O-Acetylation in GBS Pathogenesis & Immunity

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GBS is the leading agent of bacterial sepsis and meningitis in human neonates. The GBS surface capsular polysaccharide (CPS) is a major virulence factor and target of protective immunity. CPS structures of every dentified GBS serotype share in common a signature feature: a terminal alpha2->3-linked sialic acid. We have identified a major biochemical modification present in the native GBS CPS: O-acetylated of these sialic acid residues (Lewis et al. PNAS 2004). Similar modifications are known to generate novel immunogenic epitopes, modulate complement activation, and affect interactions with host leukocytes. O-acetylation was missed in >30 years of GBS research, apparently because standard protocols used for CPS purification include an NaOH treatment step removing native O-acetyl groups. As a result, current GBS vaccines in clinical trials contain a modified, non-native form of the CPS. O-acetylation of terminal alpha2->3-linked sialic acid has never been reported in any mammalian cell type, and theoretically represents a unique epitope for protective antibody against GBS. In contrast, the de-O-acetylated alpha2->3-linked sialic acid produced by NaOH treatment is a common epitopeson the surface of all human cells (in current vaccines the CPS has inadvertently modified to more closely resemble the host). Here we bring together a team of scientists with complementary expertise in GBS molecular genetics and pathogenesis, GBS epidemiology, the biochemistry and cell biology of sialic acids, and the glycobiology of bacterial capsules to comprehensively address the significance of the discovery of CPS sialic acid O-acetylation in GBS pathogenesis and immunogenicity. We will use molecular genetic and biochemical methods to create specific reagents to be tested in tissue cuture and small animal models of GBS phagocyte resistance, inflammatory activation, and passive and active immune protection. Companion analyses will be performed on GBS isolates and human sera from recent prospective seroepidemiologic studies.