Mechanism of human antibody-mediated neutralization of Marburg virus

Andrew I Flyak; Philipp A Ilinykh; Charles D Murin; Tania Garron; Xiaoli Shen; Marnie L Fusco; Takao Hashiguchi; Zachary A Bornholdt; James C Slaughter; Gopal Sapparapu; Curtis Klages; Thomas G Ksiazek; Andrew B Ward; Erica Ollmann Saphire; Alexander Bukreyev; James E Crowe Jr

doi:10.1016/j.cell.2015.01.031

Mechanism of human antibody-mediated neutralization of Marburg virus

Cell. 2015 Feb 26;160(5):893-903. doi: 10.1016/j.cell.2015.01.031.

Authors

Andrew I Flyak¹, Philipp A Ilinykh², Charles D Murin³, Tania Garron², Xiaoli Shen², Marnie L Fusco⁴, Takao Hashiguchi⁴, Zachary A Bornholdt⁴, James C Slaughter⁵, Gopal Sapparapu⁶, Curtis Klages², Thomas G Ksiazek², Andrew B Ward⁷, Erica Ollmann Saphire⁸, Alexander Bukreyev², James E Crowe Jr⁹

Affiliations

¹ Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA.
² Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, Galveston, TX 77550, USA.
³ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁵ Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN 37232, USA; Department of Biostatistics, Vanderbilt University, Nashville, TN 37232, USA.
⁶ Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN 37232, USA.
⁷ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁸ Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁹ Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: james.crowe@vanderbilt.edu.

Abstract

The mechanisms by which neutralizing antibodies inhibit Marburg virus (MARV) are not known. We isolated a panel of neutralizing antibodies from a human MARV survivor that bind to MARV glycoprotein (GP) and compete for binding to a single major antigenic site. Remarkably, several of the antibodies also bind to Ebola virus (EBOV) GP. Single-particle EM structures of antibody-GP complexes reveal that all of the neutralizing antibodies bind to MARV GP at or near the predicted region of the receptor-binding site. The presence of the glycan cap or mucin-like domain blocks binding of neutralizing antibodies to EBOV GP, but not to MARV GP. The data suggest that MARV-neutralizing antibodies inhibit virus by binding to infectious virions at the exposed MARV receptor-binding site, revealing a mechanism of filovirus inhibition.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Animals
Antibodies, Monoclonal / chemistry
Antibodies, Monoclonal / metabolism
Antibodies, Neutralizing / chemistry*
Antibodies, Neutralizing / immunology*
Antibodies, Neutralizing / isolation & purification
Antibodies, Neutralizing / metabolism
Antibodies, Viral / chemistry
Antibodies, Viral / immunology
Antibodies, Viral / metabolism
Antigen-Antibody Complex / ultrastructure*
B-Lymphocytes / immunology
Female
Humans
Immunoglobulin Fab Fragments / chemistry
Immunoglobulin Fab Fragments / metabolism
Marburg Virus Disease / immunology*
Marburgvirus / chemistry*
Marburgvirus / genetics
Marburgvirus / immunology
Models, Molecular
Mutation
Protein Structure, Tertiary
Viral Envelope Proteins / chemistry*
Viral Envelope Proteins / metabolism

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Antigen-Antibody Complex
GP-protein, Marburg virus
Immunoglobulin Fab Fragments
Viral Envelope Proteins
envelope glycoprotein, Ebola virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding