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：
10226011
负责人：
JAMES C PAULSON
金额：
$ 60.62万
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/10226011
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.

流感病毒会引起全球季节性感染和偶尔的大流行病，死亡率很高。已知人类病毒对α2-6连接的唾液酸（neuacα2-6gal）有偏爱，而鸟类病毒表现出对α2-3连接的唾液酸（NEUACα2-3GAL）的偏爱。受体特异性的这种差异被广泛认为是人口中禽病毒传播的主要物种障碍。尽管这种接收器特异性的二进制模型很有用，但它掩盖了唾液酸的真正复杂性在接收器结合特性以来影响力病毒的发展继续发展。使用数十个α2-3和α2-6连接的聚糖微阵列的使用聚糖表明，通过限制其对特定聚糖的特异性来影响病毒的影响广泛的团体。但是，对这些发现与影响力生物学相关的解释尚不确定由于几乎没有关于人类气道上实际存在的聚糖类型的信息上皮以及是否在聚糖微阵列上代表相关气道上皮。这项目旨在识别人类气道上皮细胞上结合人类影响病毒的聚糖结构并扩展聚糖阵列库以包括它们，2）确定人类的特异性和活动如何流感病毒血凝素（HAS）和神经毒素酶（NAS）在免疫选择性压力下进化为保留其与人类气道接收器互动的能力，以及3）使用收集的信息受体特异性以开发可靠的方法来分析和传播实验室中的影响力。该信息将确定受体对人类呼吸道的决定病毒，并阐明了HA和NA的性质，这导致了流行性流行病风险的风险来自偶尔感染人类的禽病毒。