H. influenzae Genes Associated with Acute Otitis Media

与急性中耳炎相关的流感嗜血杆菌基因

• 批准号: 7619008
• 负责人: JANET R GILSDORF
• 金额: $ 40.94万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619008
• 关键词: Acute; Alleles; Antigenic Variation; Antigens; Child; Chinchilla (genus); Classification; Complex; Computer Simulation; DNA Microarray Chip; Development; Disease; Ear; Ecology; Environmental Risk Factor; Exhibits; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Growth; Haemophilus Vaccines; Haemophilus influenza virulence; Haemophilus influenzae; Host Defense; Infection; Iron; Island; Modeling; Otitis Media; Pathogenesis; Pathway interactions; Pharyngeal structure; Prevalence; Prevention approach; Proteins; Respiratory System; Respiratory tract structure; Role; Testing; Trees; Vaccine Antigen; Vaccines; Variant; Virulence; Virulence Factors; bacteria characteristic; design; fitness; gene discovery; gene function; iron metabolism; middle ear; novel strategies; prevent; public health relevance

DESCRIPTION (provided by applicant): Acute otitis media results from a complex interplay of host defenses, environmental factors, and virulence characteristics of bacteria. Previous studies suggest that non-typeable Haemophilus influenza (NTHi), an important cause of acute otitis media in children, possess unique genes important in the pathogenesis of this infection. In this project, we will identify potential NTHi factors associated with otitis media using an epidemiologic approach that takes advantage of natural biologic selection. Because NTHi isolated from the middle ears of children with otitis media appear to possess specific genes offering increased bacterial fitness in the middle ear that are not required for NTHi colonization of the pharynx, we will use prevalence analysis, as performed on a whole bacterial genomic DNA microarray, to identify NTHi genes retained by otitis media strains compared to NTHi commensal strains in the pharynges of children. The Specific Aims of this project are to: I. Identify potential NTHi otitis media-associated genes by prevalence analysis, focusing on known Hi virulence genes, genes identified through in silico subtraction analysis of middle ear and throat strains, and genes within Hi genetic island 7. II. Identify polymorphisms in NTHi virulence genes that predict otitis media by testing the prevalences of the major gene alleles among ear and throat strains. III. Investigate the role of iron metabolism genes in NTHi otitis media by prevalence analysis and by exploration of the function of these genes in iron dependent NTHi growth and in NTHi iron acquisition. IV. Identify by classification tree analysis otitis media pathotypes consisting of clusters of NTHi genes that discriminate acute otitis media strains from throat strains. V. Test for virulence of NTHi lacking otitis media-associated genes in a chinchilla model as proof-of- principle that the gene discovery strategy identifies otitis media virulence genes. Identification of unique NTHi otitis media-associated factors and virulence pathways will facilitate the development of novel approaches to the prevention and treatment of NTHi otitis media that may preserve the unique ecology of NTHi in the pharynges. PUBLIC HEALTH RELEVANCE The results of this gene discovery project will identify NTHi genes that are more prevalent among otitis media NTHi strains than among commensal throat strains, and thus likely to be important in NTHi survival in the middle ear and to be associated with the disease otitis media. Proteins encoded by these genes will be attractive candidates for a multi-component NTHi vaccine, as targeting otitis media-associated antigens would be expected to reduce otitis media without greatly disturbing the ecology of NTHi in the pharynx.

描述（由申请人提供）：急性中耳炎是由宿主防御、环境因素和细菌毒力特征的复杂相互作用引起的。先前的研究表明，不可分型流感嗜血杆菌（NTHi）是儿童急性中耳炎的重要病因，其独特的基因在这种感染的发病机制中发挥着重要作用。在这个项目中，我们将利用自然生物选择的流行病学方法来识别与中耳炎相关的潜在 NTHi 因素。由于从患有中耳炎的儿童的中耳中分离出的 NTHi 似乎具有增强中耳细菌适应性的特定基因，而这些基因对于 NTHi 在咽部的定植不是必需的，因此我们将使用在整个细菌基因组 DNA 微阵列上进行的流行率分析来识别中耳炎菌株保留的 NTHi 基因，与儿童咽部中的 NTHi 共生菌株进行比较。该项目的具体目标是： 一、通过流行率分析确定潜在的 NTHi 中耳炎相关基因，重点关注已知的 Hi 毒力基因、通过中耳和咽喉菌株的计算机消减分析确定的基因以及 Hi 遗传岛 7 内的基因。通过测试耳部和咽喉毒株中主要基因等位基因的流行率，鉴定可预测中耳炎的 NTHi 毒力基因的多态性。三．通过患病率分析以及探索这些基因在铁依赖性 NTHi 生长和 NTHi 铁获取中的功能，研究铁代谢基因在 NTHi 中耳炎中的作用。四．通过分类树分析识别由 NTHi 基因簇组成的中耳炎病理类型，区分急性中耳炎菌株和咽喉菌株。 V.在龙猫模型中测试缺乏中耳炎相关基因的 NTHi 的毒力，作为基因发现策略识别中耳炎毒力基因的原理证明。鉴定独特的 NTHi 中耳炎相关因子和毒力途径将有助于开发预防和治疗 NTHi 中耳炎的新方法，从而保留咽部 NTHi 的独特生态。公共卫生相关性 该基因发现项目的结果将鉴定出 NTHi 基因，这些基因在中耳炎 NTHi 菌株中比共生咽喉菌株中更常见，因此可能对中耳 NTHi 存活很重要，并与中耳炎疾病相关。这些基因编码的蛋白质将成为多成分 NTHi 疫苗的有吸引力的候选者，因为靶向中耳炎相关抗原有望减少中耳炎，而不会极大地扰乱咽部 NTHi 的生态。