Sialic Acid O-Acetylation in GBS Pathogenesis & Immunity

GBS 发病机制中的唾液酸 O-乙酰化

• 批准号: 7017413
• 负责人: Victor Nizet
• 金额: $ 30.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-07 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017413
• 关键词: N acetylneuraminate; Streptococcus agalactiae; acetylation; active immunization; bacteria infection mechanism; bacterial capsules; bacterial genetics; bacterial meningitis; bacterial polysaccharides; clinical research; disease /disorder model; histopathology; host organism interaction; human tissue; inflammation; laboratory mouse; mass spectrometry; microorganism immunology; newborn human (0-6 weeks); phagocytes; pregnancy immunology; septicemia; serotyping; site directed mutagenesis; virulence

DESCRIPTION (provided by applicant): 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 identified 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. 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 a 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 epitope on 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 culture 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.

描述（由申请人提供）：GBS是人类新生儿中细菌败血症和脑膜炎的领先药物。 GBS表面囊囊多糖（CPS）是保护性免疫的主要毒力因子和靶标。每个已鉴定的GBS血清型的CPS结构共有一个签名特征：末端alpha2-> 3连接的唾液酸。我们已经确定了天然GBS CPS中存在的主要生化修饰：这些唾液酸残基的O-乙酰化。已知类似的修饰会产生新型的免疫原性表位，调节补体激活并影响与宿主白细胞的相互作用。在> 30年的GBS研究中遗漏了O-乙酰化，显然是因为用于CPS纯化的标准方案包括NaOH治疗步骤去除天然O-乙酰基团。结果，临床试验中的当前GBS疫苗包含一种改良的非本地形式的CPS。末端α2-> 3连接的唾液酸的O-乙酰化从未在任何哺乳动物的细胞类型中报道过，理论上代表了针对GBS的保护性抗体的独特表位。相反，NaOH处理产生的De-O-乙酰化α2-> 3连接的唾液酸是所有人类细胞表面上的一个常见表位（在当前疫苗中，CPS无意中修饰以更紧密地与宿主相似）。在这里，我们将一组科学家组成，具有GBS分子遗传学和发病机理，GBS流行病学，唾液酸的生物化学和细胞生物学以及细菌胶囊的糖生物学的互补专业知识，以理解CPS唾液酸o-含量核酸含量的意义。我们将使用分子遗传和生化方法来创建在组织培养和GBS吞噬细胞耐药性，炎症激活以及被动和主动免疫保护的小动物模型中进行测试的特定试剂。伴侣分析将对最近的前瞻性血清ePIDEMIologic研究对GBS分离株和人类血清进行。