Influenza virus receptors on human airway epithelial cells

人呼吸道上皮细胞上的流感病毒受体

基本信息

批准号：
9887570
负责人：
JAMES C PAULSON
金额：
$ 62.41万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-03 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9887570
关键词：
Agglutinins Antibodies Avian Influenza A Virus Avidity Binding Biological Assay Biology Birds Cells Chickens Drops Endothelial Cells Enzyme-Linked Immunosorbent Assay Epithelial Cells Epithelial Receptor Cell Equilibrium Erythrocytes Evolution Exhibits Galanthus Glean Goals Growth Hemagglutinin Horseradish Peroxidase Human Human Activities Immune Immunodominant Epitopes Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Influenza Hemagglutinin Kinetics Knowledge Laboratories Libraries Light Link MDCK cell Meleagris gallopavo Methods Modeling Mutation Nasal Epithelium Neuraminidase Nose Polysaccharides Population Production Property Proteins Recombinants Recovery Risk Role ST14 gene Sialic Acids Soft Palate Specificity Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Structure Surface Antigens Surveys Time Tracheal Epithelium Vaccine Production Vaccines Variant Virus Virus Receptors Virus Shedding airway epithelium base chorioallantoic membrane egg fitness flu activity improved influenzavirus lactosamine mortality novel pandemic disease preference pressure receptor receptor binding tool transmission process vaccine efficacy

项目摘要

Influenza virus causes worldwide seasonal infections and occasional pandemics with high mortality rate. Human viruses are known to have a preference for α2-6 linked sialic acids (NeuAcα2-6Gal), while avian viruses exhibit a preference for α2-3 linked sialic acids (NeuAcα2-3Gal). This difference in receptor specificity is widely considered a major species barrier for transmission of avian viruses in the human population. Although this binary model of receptor specificity has been useful, it belies the true complexity of sialic acid containing glycans on host cells and has becoming increasingly limiting since the receptor binding properties of influenza viruses continue to evolve. The use of glycan microarrays with dozens of α2-3 and α2-6 linked glycans has shown that influenza viruses evolve by restricting their specificity to specific glycans within those broad groups. However, interpretation of these findings for their relevance to influenza biology is uncertain since there is little information about the types of glycans that are actually present on human airway epithelium, and whether relevant airway epithelium glycans are represented on glycan microarrays. This project aims to identify the glycan structures on human airway epithelial cells that bind human influenza virus and expand glycan array libraries to include them, 2) to determine how the specificity and activity of human influenza virus hemagglutinins (HAs) and neuraminidases (NAs) evolve under immune selective pressure to retain their ability to interact with human airway receptors and 3) to use the information gleaned about receptor specificity to develop reliable methods for analysis and propagation of influenza in the laboratory. This information will identify receptor determinants on the human airway that are shared by human influenza viruses, and shed light on properties of the HA and NA that contribute to pandemic risk of influenza viruses from avian viruses that occasionally infect humans.

流感病毒引起世界范围内的季节性感染和偶发性大流行，死亡率很高。已知人类病毒偏爱 α2-6 连接的唾液酸 (NeuAcα2-6Gal)，而禽类病毒则偏爱 α2-6 连接的唾液酸 (NeuAcα2-6Gal)。病毒表现出对α2-3连接的唾液酸（NeuAcα2-3Gal）的偏好，这种受体特异性的差异。被广泛认为是禽流感病毒在人群中传播的主要物种障碍。尽管这种受体特异性的二元模型很有用，但它掩盖了唾液酸的真正复杂性宿主细胞上含有聚糖，并且由于受体结合特性而变得越来越受到限制使用具有数十个 α2-3 和 α2-6 连接的聚糖微阵列。聚糖已表明，流感病毒通过将其特异性限制在这些病毒中的特定聚糖而进化。然而，这些发现与流感生物学的相关性的解释尚不确定。因为关于人类呼吸道中实际存在的聚糖类型的信息很少上皮，以及相关的气道上皮聚糖是否出现在聚糖微阵列上。该项目旨在识别人类呼吸道上皮细胞上与人类流感病毒结合的聚糖结构并扩展聚糖阵列文库以包含它们，2) 确定人类聚糖的特异性和活性如何流感病毒血凝素（HA）和神经氨酸酶（NA）在免疫选择压力下进化保留与人类气道受体相互作用的能力，并且 3) 使用收集到的信息受体特异性，以开发在实验室中分析和传播流感的可靠方法。该信息将识别人类流感所共有的人类气道上的受体决定因素病毒，并揭示了导致流感病毒大流行风险的 HA 和 NA 的特性来自偶尔感染人类的禽流感病毒。