Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein
Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein
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DOI：
10.1038/s41467-017-01708-9
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发表时间：
2017-11-16
影响因子：
16.6
通讯作者：
McLellan, Jason S.
中科院分区：
文献类型：
--
作者：
Battles, Michael B.;Mas, Vicente;McLellan, Jason S.
人类偏肺病毒(HMPV)是幼儿毛细支气管炎的常见病因。其F糖蛋白介导病毒-细胞膜融合，是中和抗体的主要靶点。在亚稳态融合前构象中不能产生重组hMPV F糖蛋白阻碍了结构和免疫学研究。在这里，我们设计了一个预融合稳定的hMPV F胞外结构域，并确定了它的晶体结构，分辨率为2.6埃。这种结构揭示了依赖于应变的酸诱导融合的分子决定因素，以及对融合前和融合后构象重折叠的见解。融合前hMPV F顶端的致密多聚糖屏障表明，宿主免疫反应可能不会激发针对该位点的抗体，这一点已被人免疫球蛋白耗竭研究和小鼠免疫证实。这是与人类呼吸道合胞病毒(HRSV)融合前F的主要区别，我们的结果应该有助于开发有效的hMPV候选疫苗。
Human metapneumovirus (hMPV) is a frequent cause of bronchiolitis in young children. Its F glycoprotein mediates virus-cell membrane fusion and is the primary target of neutralizing antibodies. The inability to produce recombinant hMPV F glycoprotein in the metastable pre-fusion conformation has hindered structural and immunological studies. Here, we engineer a pre-fusion-stabilized hMPV F ectodomain and determine its crystal structure to 2.6 angstrom resolution. This structure reveals molecular determinants of strain-dependent acid-induced fusion, as well as insights into refolding from pre- to post-fusion conformations. A dense glycan shield at the apex of pre- fusion hMPV F suggests that antibodies against this site may not be elicited by host immune responses, which is confirmed by depletion studies of human immunoglobulins and by mouse immunizations. This is a major difference with pre-fusion F from human respiratory syncytial virus (hRSV), and collectively our results should facilitate development of effective hMPV vaccine candidates.