2. Academic Validation
  3. Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress

Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress

  • Cell. 2015 Nov 19;163(5):1095-1107. doi: 10.1016/j.cell.2015.10.050.
Julie M Fox 1,  Feng Long 2,  Melissa A Edeling 3,  Hueylie Lin 1,  Mareike K S van Duijl-Richter 4,  Rachel H Fong 5,  Kristen M Kahle 5,  Jolanda M Smit 4,  Jing Jin 6,  Graham Simmons 6,  Benjamin J Doranz 5,  James E Crowe Jr 7,  Daved H Fremont 3,  Michael G Rossmann 2,  Michael S Diamond 8
Affiliations

Affiliations

  • 1 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 2 Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
  • 3 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 4 University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
  • 5 Integral Molecular, Inc., Philadelphia, PA 19104, USA.
  • 6 Blood Systems Research Institute, San Francisco, CA 94118, USA.
  • 7 Departments of Pediatrics, Pathology, Microbiology, and Immunology and the Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN 37235, USA.
  • 8 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: diamond@wusm.wustl.edu.
PMID: 26553503 DOI: 10.1016/j.cell.2015.10.050
Abstract

We screened a panel of mouse and human monoclonal antibodies (MAbs) against chikungunya virus and identified several with inhibitory activity against multiple alphaviruses. Passive transfer of broadly neutralizing MAbs protected mice against Infection by chikungunya, Mayaro, and O'nyong'nyong alphaviruses. Using alanine-scanning mutagenesis, loss-of-function recombinant proteins and viruses, and multiple functional assays, we determined that broadly neutralizing MAbs block multiple steps in the viral lifecycle, including entry and egress, and bind to a conserved epitope on the B domain of the E2 glycoprotein. A 16 Å resolution cryo-electron microscopy structure of a Fab fragment bound to CHIKV E2 B domain provided an explanation for its neutralizing activity. Binding to the B domain was associated with repositioning of the A domain of E2 that enabled cross-linking of neighboring spikes. Our results suggest that B domain antigenic determinants could be targeted for vaccine or antibody therapeutic development against multiple alphaviruses of global concern.

Figures
Products