Influenza virus receptors on human airway epithelial cells

 描述(申请人提供)：流感病毒引起世界范围内的季节性感染和偶尔的大流行，死亡率高。已知人类病毒偏爱2-6连接唾液酸(NeuAc2-6Gal)，而禽类病毒则偏爱2-3连接唾液酸(NeuAc2-3Gal)。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。虽然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唾液酸多糖的真正复杂性，由于最近的流感病毒表现出与禽类病毒不同的混合特异性，使用标准的受体特异性评估方法，它变得越来越有限。使用含有数十个2-3和2-6连接的多糖的葡聚糖微阵列表明，流感病毒在识别这些广泛群体中的单个多糖的能力方面表现出显著的差异。然而，对 这些发现令人困惑的是，几乎没有关于人类呼吸道上皮实际存在的多糖类型的信息，以及相关的多糖是否存在于多糖微阵列上。为了解决这一知识空白，我们打算1)分析人类呼吸道上皮细胞上的糖链结构，2)构建这些糖链的合成文库，以构建定制的糖链微阵列，3)评估人类流感病毒血凝素(HAS)和神经氨酸酶(NAS)的特异性，以确定支持它们在人类中传播的受体结合特性。这些信息将确定人类呼吸道上由在人类群体中传播的人类流感病毒所共有的接受决定因素，并阐明导致偶尔感染人类的禽流感病毒大流行风险的HA和NA的特性。

 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.