NTHi LPS: virulence factor and vaccine candidate

NTHi LPS：毒力因子和候选疫苗

• 批准号: 7099463
• 负责人: RICHARD GOLDSTEIN
• 金额: $ 35.14万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099463
• 关键词: Haemophilus influenzae; Haemophilus influenzae vaccines; bacteria infection mechanism; bacterial cytopathogenic effect; bacterial genetics; chinchilla; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; gene expression; glycolipids; glycoproteins; host organism interaction; lipopolysaccharides; mass spectrometry; microarray technology; otitis media; phenotype; vaccine development; virulence

DESCRIPTION (provided by applicant): Nontypable Haemophilus influenzae (NTHi) is a major pathogen in otitis media. It appears to be especially prominent in children with recurrent episodes of acute otitis media (AOM). The broad, long-term objective of this proposal is to define the various roles of lipopolysaccharide (LPS) as a virulence factor in pathogenesis of AOM, with the ultimate goal of developing an LPS inner-core glycoconjugate vaccine against NTHi. Prior efforts in vaccine development have been limited by diversifying selective pressures on surface exposed epitopes of NTHi; however, the use of conserved LPS inner-core may circumvent this limitation. The first specific aim is to identify phenotypic and genotypic changes in NTHi LPS expression during transition from asymptomatic carriage to middle ear disease, in order to identify LPS glycoforms that may have potential as additional vaccine target candidates. Animal modeling in conjunction with mass spectrometry techniques and microarray technology should enable the identification of such critical LPS glycoforms. Secondly, interaction between newly resolved LPS glycoforms and host defense mechanisms will be assessed, by flow cytometry and ELISA techniques. The final aim is to determine whether truncated inner-core LPS oligosaccharide structures, when conjugated to a protein carrier, are immunogenic and protective against experimental OM due to both homologous and heterologous isolates of NTHi in a chinchilla animal model. This collaboration between Boston Univ. Medical School, Institute for Biological Sciences NRC-Canada and Oxford University Institute for Molecular Medicine brings together synergistic expertise in microbial genetics and population biology, immunology, LPS structural chemistry, and animal modeling.

描述（由申请人提供）：不富裕的流感嗜血杆菌（NTHI）是中耳炎的主要病原体。在患有急性中耳炎（AOM）复发性发作的儿童中，它似乎特别突出。该提议的广泛长期目标是将脂多糖（LPS）的各种作用定义为AOM发病机理中的毒力因子，其最终目标是开发LPS内核心糖缀合物疫苗针对NTHI。通过在NTHI表面表面表现上多样化的选择性压力多样化，疫苗开发方面的先前努力受到限制；但是，内部核心保守的LPS的使用可能会规避此限制。第一个具体目的是鉴定从无症状托架到中耳疾病的过渡期间NTHI LPS表达的表型和基因型变化，以鉴定可能具有额外疫苗目标候选物的LPS糖型。与质谱技术和微阵列技术结合的动物建模应能够鉴定这种关键的LPS糖型。其次，将通过流式细胞仪和ELISA技术评估新解决的LP糖型与宿主防御机制之间的相互作用。最终目的是确定截短的内部核心LPS寡糖结构在与蛋白质载体结合时是否具有免疫原性和保护性，以防止实验性OM，这是由于丁香动物模型中NTHI的同源和异源分离株。波士顿大学之间的合作。医学院，生物科学研究所NRC-Canada和牛津大学分子医学研究所汇集了微生物遗传学和人群生物学，免疫学，LPS结构化学和动物建模方面的协同专业知识。