Influenza virus receptors on human airway epithelial cells

 描述（由申请人提供）：流感病毒引起全球季节性感染和偶尔的大流行，死亡率高。已知人类病毒偏好于β 2-6连接的唾液酸（NeuAc β 2- 6 Gal），而禽类病毒表现出对β 2-3连接的唾液酸（NeuAc β 2-3Gal）的偏好。这种受体特异性的差异被广泛认为是禽类病毒在人群中传播的主要种属障碍。尽管这种受体特异性的二元模型是有用的，但它掩盖了宿主细胞上含有唾液酸的聚糖的真实复杂性，它变得越来越有限，因为最近的流感病毒显示出混合特异性，其使用评估受体特异性的标准测定法与禽病毒没有区别。使用具有数十个β 2-3和β 2-6连接的聚糖的聚糖微阵列已经揭示，流感病毒在它们识别这些广泛组内的单个聚糖的能力方面表现出显著差异。然而，对 这些发现被以下事实所混淆：关于实际存在于人气道上皮上的聚糖类型以及相关聚糖是否在聚糖微阵列上呈现的信息很少。为了解决这一知识空白，我们打算1）分析人气道上皮细胞上的聚糖结构，2）构建这些聚糖的合成文库，用于构建定制聚糖微阵列，3）评价人流感病毒血凝素（HA）和神经氨酸酶（NA）的特异性，以鉴定支持其在人体内传播能力的受体结合特性。这些信息将确定在人群中传播的人流感病毒所共有的人呼吸道受体决定簇，并阐明HA和NA的特性，这些特性有助于偶尔感染人类的禽流感病毒的大流行风险。

 DESCRIPTION (provided by applicant): Influenza virus causes worldwide seasonal infections and occasional pandemics with high mortality rate. Human viruses are known to have a preference for 2-6 linked sialic acids (NeuAc2-6Gal), while avian viruses exhibit a preferenc for 2-3 linked sialic acids (NeuAc2-3Gal). 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 o sialic acid containing glycans on host cells, it has becoming increasingly limiting since recent influenza viruses exhibit mixed specificities that are not distinct from avian viruses using standard assays of assessing receptor specificity. The use of glycan microarrays with dozens of 2-3 and 2-6 linked glycans has revealed that influenza viruses exhibit dramatic differences i their ability to recognize individual glycans within those broad groups. However, interpretation of these findings is confounded by the fact that there is little information on the types of glycans that are actually present on human airway epithelium, and whether the relevant glycans are represented on glycan microarrays. To address this gap in knowledge, we intend to 1) analyze the glycan structures on human airway epithelial cells, 2) to build a synthetic library of these glycans for constructing a custom glycan microarray, and 3) to evaluate the specificity of human influenza virus hemagglutinins (HAs) and neuraminidases (NAs) to identify receptor-binding properties that support their ability to transmit in humans. This information will identify recepto determinants on the human airway that are shared by human influenza viruses that transmit in the human population, 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.