The soft palate is an important site of adaptation for transmissible influenza viruses.
The soft palate is an important site of adaptation for transmissible influenza viruses.
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DOI：
10.1038/nature15379
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发表时间：
2015-10-01
期刊：
影响因子：
64.8
通讯作者：
Subbarao K
中科院分区：
文献类型：
--
作者：
Lakdawala SS;Jayaraman A;Halpin RA;Lamirande EW;Shih AR;Stockwell TB;Lin X;Simenauer A;Hanson CT;Vogel L;Paskel M;Minai M;Moore I;Orandle M;Das SR;Wentworth DE;Sasisekharan R;Subbarao K
甲型流感病毒引起季节性流行病和散发性流行病，对公共卫生构成重大威胁。他们的流行病学成功依赖于人与人之间的空气传播；然而，控制甲型流感病毒空气传播的病毒特性很复杂。甲型流感病毒感染是通过病毒血凝素 (HA) 与细胞表面糖蛋白末端附着的 α2,3 或 α2,6 唾液酸结合介导的。人类甲型流感病毒优先结合α2,6-连接的唾液酸，而禽甲型流感病毒则结合气道上皮细胞上复杂聚糖上的α2,3-连接的唾液酸。从历史上看，优先与α2,3连接的唾液酸相关的甲型流感病毒尚未通过雪貂中的空气传播途径有效传播。在这里，我们观察到 2009 年大流行的 H1N1 (H1N1pdm) 病毒 (A/California/07/2009) 的高效空气传播，该病毒被设计为优先结合 α2,3 连接的唾液酸。空气传播与病毒的快速选择有关，单个 HA 位点发生变化，使其与长链 α2,6 连接的唾液酸结合，而不丧失 α2,3 连接的唾液酸结合。这种传染性病毒在感染后 24 小时内出现在实验感染的雪貂体内，并且在软腭中显着富集，其中长链 α2,6 连接的唾液酸在鼻咽表面占主导地位。值得注意的是，长链 α2,6 连接的唾液酸在雪貂、猪和人类软腭中是保守的。使用这种病毒的功能丧失方法，我们证明雪貂软腭（流感动物模型中通常不会取样的组织）能够快速选择具有人类受体（α2,6-连接唾液酸）偏好的可传播甲型流感病毒。
Influenza A viruses pose a major public health threat by causing seasonal epidemics and sporadic pandemics. Their epidemiological success relies on airborne transmission from person to person; however, the viral properties governing airborne transmission of influenza A viruses are complex. Influenza A virus infection is mediated via binding of the viral haemagglutinin (HA) to terminally attached α2,3 or α2,6 sialic acids on cell surface glycoproteins. Human influenza A viruses preferentially bind α2,6-linked sialic acids whereas avian influenza A viruses bind α2,3-linked sialic acids on complex glycans on airway epithelial cells,. Historically, influenza A viruses with preferential association with α2,3-linked sialic acids have not been transmitted efficiently by the airborne route in ferrets,. Here we observe efficient airborne transmission of a 2009 pandemic H1N1 (H1N1pdm) virus (A/California/07/2009) engineered to preferentially bind α2,3-linked sialic acids. Airborne transmission was associated with rapid selection of virus with a change at a single HA site that conferred binding to long-chain α2,6-linked sialic acids, without loss of α2,3-linked sialic acid binding. The transmissible virus emerged in experimentally infected ferrets within 24 hours after infection and was remarkably enriched in the soft palate, where long-chain α2,6-linked sialic acids predominate on the nasopharyngeal surface. Notably, presence of long-chain α2,6-linked sialic acids is conserved in ferret, pig and human soft palate. Using a loss-of-function approach with this one virus, we demonstrate that the ferret soft palate, a tissue not normally sampled in animal models of influenza, rapidly selects for transmissible influenza A viruses with human receptor (α2,6-linked sialic acids) preference.