Sialic Acid O-Acetylation in GBS Pathogenesis & Immunity

GBS是新生儿细菌性败血症和脑膜炎的主要病原体。GBS表面囊膜 多糖（CPS）是一种主要的毒力因子和保护性免疫的靶点。CPS结构， 鉴定的GBS血清型共有一个标志功能：末端α 2->3-连接的唾液酸。我们 已经鉴定了天然GBS CPS中存在的主要生化修饰：这些唾液酸的O-乙酰化 酸残基（刘易斯等人，PNAS 2004）。已知类似的修饰产生新的免疫原性 表位，调节补体激活，并影响与宿主白细胞的相互作用。O-乙酰化是 在GBS研究的30年中，显然是因为用于CPS纯化的标准方案 包括除去天然O-乙酰基NaOH处理步骤。因此，目前的GBS疫苗 临床试验包含CPS的改良的非天然形式。末端α 2->3-连接的O-乙酰化 唾液酸从未在任何哺乳动物细胞类型中报道过，理论上代表了一种独特的 抗GBS保护性抗体的表位。相比之下，去-O-乙酰化的α 2->3-连接的唾液酸 是所有人类细胞表面的共同表位（在目前的疫苗中， CPS无意中修改为更接近主机）。在这里，我们汇集了一个团队， 在GBS分子遗传学和发病机制，GBS流行病学， 唾液酸的生物化学和细胞生物学，以及细菌荚膜的糖生物学， 全面阐述了CPS唾液酸O-乙酰化在GBS中发现的意义 致病性和免疫原性。我们将使用分子遗传学和生物化学方法来创造 在组织培养和GBS吞噬细胞抗性的小动物模型中测试的特定试剂， 炎症激活以及被动和主动免疫保护。将进行伴随分析 对最近前瞻性血清流行病学研究中的GBS分离株和人血清的影响。

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.