Sialic Acid O-Acetylation in GBS Pathogenesis & Immunity

GBS 发病机制中的唾液酸 O-乙酰化

基本信息

批准号：
7933163
负责人：
Victor Nizet
金额：
$ 8万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-02-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7933163
关键词：
Acetylation Acetylesterase Active Immunization Address Adherence Affect Anabolism Animal Model Antibodies Antigens Bacterial Capsules Biochemical Biochemistry Biology Cell surface Cells Cellular biology Chemicals Clinical Trials Common Epitope Companions Complement Complement Activation Conjugate Vaccines Development Disease Encapsulated Endothelial Cells Epidemiology Epithelial Epitopes Evolution Family Focus Groups Genes Genetic Glycobiology Human Immune Immune Sera Immunity Immunoglobulin G Inflammation Mediators Inflammatory Investigation Leukocytes Link Mammalian Cell Mass Spectrum Analysis Meningitis Methods Modification Molecular Genetics Mus N-Acetylneuraminic Acid Neonatal Operon Pathogenesis Pathogenicity Pathway interactions Phagocytes Phagocytosis Phase Phenotype Play Polysaccharides Preparation Principal Investigator Procedures Property Proteins Protocols documentation Publishing Reagent Reporting Research Research Personnel Resistance Risk Factors Role Scientist Sepsis Seroepidemiologic Studies Serotyping Serum Sialic Acids Side Site-Directed Mutagenesis Streptococcal Infections Streptococcus Group B Streptococcus vaccine Structure Surface Surveys System Testing Tissues Treatment Step Vaccine Design Vaccines Variant Virulence Virulence Factors base capsule cell type human disease immunogenic immunogenicity neonate novel pathogen pregnant prospective pup response sugar vaccine development

项目摘要

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.

GBS是人类新生儿中细菌败血症和脑膜炎的主要药物。 GBS表面囊多糖（CPS）是保护性免疫的主要毒力因子和靶标。 CPS结构牙齿的GBS血清型在共同的签名特征中共享：末端α2-> 3连接的唾液酸。我们已经确定了本机GBS CPS中存在的主要生化修饰：这些唾液的O-乙酰化酸残基（Lewis等人PNAS 2004）。已知类似的修改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。 O-乙酰化是错过了> 30年的GBS研究，显然是因为用于CPS纯化的标准协议包括一个NaOH治疗步骤去除天然的O-乙酰基。结果，当前的GBS疫苗临床试验包含CPS的修改，非本地形式。末端alpha2-> 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得到报道，理论上代表了独特的保护性GB的保护性抗体的表位。相反，脱乙酰化α2-> 3连接的唾液酸 NaOH处理产生的是所有人类细胞表面的常见表位（在当前疫苗中 CP无意中修改以更类似于主机）。在这里，我们将一个团队组成具有GBS分子遗传学和发病机理的互补专业知识的科学家，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全面地解决了GBS中发现CPS唾液酸O-乙酰化的重要性发病机理和免疫原性。我们将使用分子遗传和生化方法来创建在组织切口和GBS吞噬细胞耐药性的小动物模型中进行测试的特定试剂，炎症激活以及被动和主动的免疫保护。将进行伴侣分析从最近的前瞻性血清ePIDEMIologic研究中的GBS分离株和人类血清上。