Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Cell Host Microbe. 2019 Dec 11;26(6):729-738.e4. doi: 10.1016/j.chom.2019.10.002. Epub 2019 Nov 19.
Influenza virus neuraminidase (NA) is a major target for small-molecule antiviral drugs. Antibodies targeting the NA surface antigen could also inhibit virus entry and egress to provide host protection. However, our understanding of the nature and range of target epitopes is limited because of a lack of human antibody structures with influenza neuraminidase. Here, we describe crystal and cryogenic electron microscopy (cryo-EM) structures of NAs from human-infecting avian H7N9 viruses in complex with five human anti-N9 antibodies, systematically defining several antigenic sites and antibody epitope footprints. These antibodies either fully or partially block the NA active site or bind to epitopes distant from the active site while still showing neuraminidase inhibition. The inhibition of antibodies to NAs was further analyzed by glycan array and solution-based NA activity assays. Together, these structural studies provide insights into protection by anti-NA antibodies and templates for the development of NA-based influenza virus vaccines and therapeutics.
流感病毒神经氨酸酶（NA）是小分子抗病毒药物的主要靶标。针对 NA 表面抗原的抗体也可以抑制病毒进入和离开宿主，从而提供宿主保护。然而，由于缺乏具有流感神经氨酸酶的人抗体结构，我们对靶表位的性质和范围的了解有限。在这里，我们描述了与来自感染人类的禽流感 H7N9 病毒的五个人类抗 N9 抗体复合的 NAs 的晶体和低温电子显微镜（cryo-EM）结构，系统地定义了几个抗原位点和抗体表位足迹。这些抗体要么完全或部分阻断 NA 活性位点，要么与活性位点遥远的表位结合，同时仍显示神经氨酸酶抑制。通过聚糖阵列和基于溶液的 NA 活性测定进一步分析了抗体对 NAs 的抑制作用。这些结构研究共同为抗 NA 抗体的保护提供了深入了解，并为基于 NA 的流感病毒疫苗和治疗药物的开发提供了模板。
