Entry of Influenza A Virus with α2,6-Linked Sialic Acid Binding Preference Requires Host Fibronectin
Entry of Influenza A Virus with α2,6-Linked Sialic Acid Binding Preference Requires Host Fibronectin
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DOI：
10.1128/jvi.01166-12
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发表时间：
2012-10-01
影响因子：
5.4
通讯作者：
Poon, Leo L. M.
中科院分区：
文献类型：
--
作者：
Leung, Horasis S. Y.;Li, Olive T. W.;Poon, Leo L. M.
甲型流感病毒的受体结合特异性是病毒趋向性和宿主特异性的主要决定因素之一。一般来说，禽病毒血凝素倾向于与α 2,3-链唾液酸结合，而人病毒血凝素倾向于与α 2,6-链唾液酸结合。在这里，我们证明宿主纤维连接蛋白在一些甲型流感病毒的生命周期中起重要作用。用抗纤维连接蛋白抗体或纤维连接蛋白特异性小干扰RNA处理细胞可抑制人H1N1甲型流感病毒的病毒复制。引人注目的是，在感染H5N1病毒的细胞中无法观察到这些抑制作用。通过使用反向遗传学技术，我们观察到受体结合特异性，而不是血凝素亚型的起源，是造成这种差异抑制作用的原因。将血凝素的结合偏好从α 2,6-链唾液酸改变为α 2,3-链唾液酸，可使病毒对抗纤维连接蛋白抗体产生抗性，反之亦然。我们进一步的表征表明，抗纤维连接蛋白抗体作用于病毒复制周期的早期阶段，但它对甲型流感病毒与细胞表面的初始结合没有影响。我们的后续研究进一步表明，抗纤维连接蛋白抗体可以阻断流感病毒的附着后进入。总之，这些结果表明，流感病毒血凝素的唾液酸结合偏好可以调节病毒进入途径的偏好，这表明人流感病毒和禽流感病毒的进入存在微妙的差异。
The receptor binding specificity of influenza A virus is one of the major determinants of viral tropism and host specificity. In general, avian viral hemagglutinin prefers to bind to alpha 2,3-linked sialic acid, whereas the human viral hemagglutinin prefers to bind to alpha 2,6-linked sialic acid. Here, we demonstrate that host fibronectin protein plays an important role in the life cycle of some influenza A viruses. Treating cells with anti-fibronectin antibodies or fibronectin-specific small interfering RNA can inhibit the virus replication of human H1N1 influenza A viruses. Strikingly, these inhibitory effects cannot be observed in cells infected with H5N1 viruses. By using reverse genetics techniques, we observed that the receptor binding specificity, but not the origin of the hemagglutinin subtype, is responsible for this differential inhibitory effect. Changing the binding preference of hemagglutinin from alpha 2,6-linked sialic acid to alpha 2,3-linked sialic acid can make the virus resistant to the anti-fibronectin antibody treatment and vice versa. Our further characterizations indicate that anti-fibronectin antibody acts on the early phase of viral replication cycle, but it has no effect on the initial binding of influenza A virus to cell surface. Our subsequent investigations further show that anti-fibronectin antibody can block the postattachment entry of influenza virus. Overall, these results indicate that the sialic acid binding preference of influenza viral hemagglutinin can modulate the preferences of viral entry pathways, suggesting that there are subtle differences between the virus entries of human and avian influenza viruses.