Influenza virus receptors on human airway epithelial cells

人呼吸道上皮细胞上的流感病毒受体

• 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
• 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

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尔的大流行，死亡率很高。 已知人类病毒偏爱α2-6连接唾液酸(NeuAcα2-6Gal)，而禽类病毒 病毒表现出对α2-3连接唾液酸(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类种群中传播的主要物种障碍。 尽管这种受体专一性的二元模型很有用，但它掩盖了唾液酸的真正复杂性。 在宿主细胞上含有多糖，并且由于受体结合特性而变得越来越有限 流感病毒的数量仍在继续进化。使用与数十个α2-3和α2-6相连的葡聚糖微阵列 多糖已经表明，流感病毒的进化是通过将其特异性限制在那些 广泛的群体。然而，对这些发现与流感生物学的相关性的解释尚不确定。 因为关于人体呼吸道中实际存在的多糖类型的信息很少 上皮细胞，以及相关的呼吸道上皮多糖是否存在于多聚糖微阵列上。这 该项目旨在鉴定与人类流感病毒结合的人呼吸道上皮细胞上的糖链结构 并扩展糖链阵列文库以包括它们，2)确定人的特异性和活性 流感病毒血凝素(Has)和神经氨酸酶(Nas)在免疫选择性压力下进化 保留它们与人类呼吸道受体相互作用的能力，以及3)使用收集到的信息 受体特异性，以开发可靠的方法，在实验室分析和繁殖流感。 这一信息将确定人类呼吸道上与人类流感共享的受体决定因素 并阐明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类病毒。