Journal article
A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface
S Bangaru, S Lang, M Schotsaert, HA Vanderven, X Zhu, N Kose, R Bombardi, JA Finn, SJ Kent, P Gilchuk, I Gilchuk, HL Turner, A García-Sastre, S Li, AB Ward, IA Wilson, JE Crowe
Cell | CELL PRESS | Published : 2019
Abstract
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 a..
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Awarded by National Institutes of Health
Funding Acknowledgements
We thank Henry Tien from the robotics core in the Wilson laboratory for automated crystal screening and Wenli Yu and Yuanzi Huang in the Wilson laboratory for technical support. We thank Rachel Nargi and Rob Carnahan at Vanderbilt for help with mAb production and sequence analysis and Ryan Irving for help with mouse studies. This work was supported by grants from the NIH U19 AI117905 (to J.E.C.), R56 AI127371 (to I.A.W.), and P01 AI097092 (to A.G.-S.) and NIH contracts HHSN272201400024C (to J.E.C.) and HHSN272201400008C (to A.G.-S.). The project described was supported by CTSA award No. UL1 TR002243 from NCATS. Vanderbilt University Medical Center used the non-clinical and pre-clinical services program offered by the NIAID through Contract No. HHSN27220170041I to determine the in vivo activity of FluA-20 in mouse models of influenza conducted by Dr. Jonna Westover at Utah State University. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS, NCATS, NIAID or NIH. X-ray diffraction data were collected at the Advanced Photon Source beamline 23ID-B (GM/CA CAT) and the Stanford Synchrotron Radiation Lightsource beamline 11-1. GM/CA@ APS is funded in whole or in part with federal funds from the NCI (ACB-12002) and the NIGMS (AGM-12006). This research used resources of the Advanced Photon Source, a U.S. DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. DOE, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH, NIGMS (including P41GM103393).