A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface
A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface
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DOI：
10.1016/j.cell.2019.04.011
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发表时间：
2019-05-16
期刊：
影响因子：
64.5
通讯作者：
Crowe, James E., Jr.
中科院分区：
文献类型：
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作者：
Bangaru, Sandhya;Lang, Shanshan;Crowe, James E., Jr.
在这里，我们描述了一种天然存在的人类抗体 (Ab) FluA-20 的发现，它可以识别血凝素 (HA) 头域上的一个新的脆弱位点，并与大多数甲型流感病毒发生反应。具有 H1 和 H3 头域的 FluA-20 的结构表征揭示了 HA 三聚体界面中的一个新表位，表明三聚体 HA 蛋白以前未被识别的动态特征。 FluA-20 识别的关键 HA 残基在大多数甲型流感病毒亚型中仍然保守，这解释了该抗体的非凡广度。该抗体可快速破坏 HA 蛋白三聚体的完整性，抑制培养物中病毒的细胞间传播，并在用作预防或治疗时保护小鼠免受 H1N1、H3N2、H5N1 或 H7N9 亚型病毒的攻击。 FluA-20 Ab 在流感 HA 头域三聚体界面中发现了一个极其保守的保护性决定簇，这是抗流感治疗和疫苗的一个意想不到的新靶点。
Here, we describe the discovery of a naturally occurring human antibody (Ab), FluA-20, that recognizes a new site of vulnerability on the hemagglutinin (HA) head domain and reacts with most influenza A viruses. Structural characterization of FluA-20 with H1 and H3 head domains revealed a novel epitope in the HA trimer interface, suggesting previously unrecognized dynamic features of the trimeric HA protein. The critical HA residues recognized by FluA-20 remain conserved across most subtypes of influenza A viruses, which explains the Ab's extraordinary breadth. The Ab rapidly disrupted the integrity of HA protein trimers, inhibited cell-to-cell spread of virus in culture, and protected mice against challenge with viruses of H1N1, H3N2, H5N1, or H7N9 subtypes when used as prophylaxis or therapy. The FluA-20 Ab has uncovered an exceedingly conserved protective determinant in the influenza HA head domain trimer interface that is an unexpected new target for anti-influenza therapeutics and vaccines.