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针对靶向融合后稳定表位的流感病毒血凝素抗体的跨群识别的结构基础。

Structural basis for cross-group recognition of an influenza virus hemagglutinin antibody that targets postfusion stabilized epitope.

机构信息

Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan.

Department of Life Science and Medical Bioscience, Waseda University, Shinjuku, Tokyo, Japan.

出版信息

PLoS Pathog. 2023 Aug 9;19(8):e1011554. doi: 10.1371/journal.ppat.1011554. eCollection 2023 Aug.

DOI:10.1371/journal.ppat.1011554
PMID:37556494
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10411744/
Abstract

Plasticity of influenza virus hemagglutinin (HA) conformation increases an opportunity to generate conserved non-native epitopes with unknown functionality. Here, we have performed an in-depth analysis of human monoclonal antibodies against a stem-helix region that is occluded in native prefusion yet exposed in postfusion HA. A stem-helix antibody, LAH31, provided IgG Fc-dependent cross-group protection by targeting a stem-helix kinked loop epitope, with a unique structure emerging in the postfusion state. The structural analysis and molecular modeling revealed key contact sites responsible for the epitope specificity and cross-group breadth that relies on somatically mutated light chain. LAH31 was inaccessible to the native prefusion HA expressed on cell surface; however, it bound to the HA structure present on infected cells with functional linkage to the Fc-mediated clearance. Our study uncovers a novel non-native epitope that emerges in the postfusion HA state, highlighting the utility of this epitope for a broadly protective antigen design.

摘要

流感病毒血凝素（HA）构象的可塑性增加了产生具有未知功能的保守非天然表位的机会。在这里，我们对针对茎-螺旋区域的人源单克隆抗体进行了深入分析，该区域在天然融合前被掩盖，但在融合后 HA 中暴露。一种茎-螺旋抗体，LAH31，通过靶向茎-螺旋弯曲环表位提供 IgG Fc 依赖性跨组保护，该表位在融合后状态下具有独特的结构。结构分析和分子建模揭示了负责表位特异性和跨组广度的关键接触位点，这依赖于体细胞突变的轻链。LAH31无法与细胞表面表达的天然融合前 HA 结合；然而，它与感染细胞上存在的 HA 结构结合，并与 Fc 介导的清除功能相关。我们的研究揭示了融合后 HA 状态下出现的一种新的非天然表位，突出了该表位在广泛保护性抗原设计中的应用价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/f9a2144b20c6/ppat.1011554.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/c4ab8225b4f8/ppat.1011554.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/255eabb9a3f2/ppat.1011554.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/b22896b4abad/ppat.1011554.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/f56548bb74de/ppat.1011554.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/f9a2144b20c6/ppat.1011554.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/c4ab8225b4f8/ppat.1011554.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/255eabb9a3f2/ppat.1011554.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/b22896b4abad/ppat.1011554.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/f56548bb74de/ppat.1011554.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c29b/10411744/f9a2144b20c6/ppat.1011554.g005.jpg

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