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Polyreactive Broadly Neutralizing B Cells are Selected to Provide Defense Against Pandemic Threat Influenza Viruses

43 Pages Posted: 30 Jun 2020 Sneak Peek Status: Under Review

See all articles by Jenna J. Guthmiller

Jenna J. Guthmiller

University of Chicago - Department of Medicine

Linda Yu-Ling Lan

University of Chicago - Committee on Immunology

Monica Fernández-Quintero

The Scripps Research Institute - Center for Molecular Biosciences Innsbruck

Julianna Han

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Dalia Bitar

University of Chicago - Department of Medicine

Natalie J. Hamel

University of Chicago - Department of Medicine

Olivia Stovicek

University of Chicago - Department of Medicine

Le Li

University of Chicago - Department of Medicine

Micah Tepora

University of Chicago - Department of Medicine

Carole Henry

University of Chicago - Department of Medicine

Karlynn E. Neu

University of Chicago - Department of Medicine

Haley L. Dugan

University of Chicago - Committee on Immunology

Yao-Qing Chen

University of Chicago - Department of Medicine

Sean T. H. Liu

Icahn School of Medicine at Mount Sinai - Department of Microbiology

Christopher T. Stamper

University of Chicago - Committee on Immunology

Nai-Ying Zheng

University of Chicago - Department of Medicine

Min Huang

University of Chicago - Department of Medicine

Anna-Karin E. Palm

University of Chicago - Department of Medicine

Adolfo García-Sastre

Icahn School of Medicine at Mount Sinai - Department of Microbiology

Raffael Nachbagauer

Icahn School of Medicine at Mount Sinai - Department of Microbiology

Peter Palese

Icahn School of Medicine at Mount Sinai - Department of Microbiology

Lynda Coughlan

Icahn School of Medicine at Mount Sinai - Department of Microbiology

Florian Krammer

Icahn School of Medicine at Mount Sinai - Department of Microbiology

Andrew B. Ward

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Klaus R. Liedl

University of Innsbruck - Center for Molecular Biosciences Innsbruck

Patrick C. Wilson

University of Chicago - Department of Medicine

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Abstract

Polyreactivity is the ability of a single antibody to bind to multiple molecularly distinct antigens and is a common feature of antibodies induced upon pathogen exposure. However, little is known about the role of polyreactivity during anti-influenza virus antibody responses. By comprehensively analyzing more than 500 monoclonal antibodies (mAbs) derived from B cells induced by numerous influenza virus vaccines and infections, we find mAbs targeting conserved neutralizing influenza virus hemagglutinin epitopes are polyreactive. Polyreactive mAbs are preferentially induced by novel viral exposures due to their broad viral binding breadth. Polyreactivity augments mAb viral binding strength by increasing antibody flexibility, allowing for adaption to imperfectly conserved epitopes. Lastly, we found affinity-matured polyreactive B cells were typically derived from germline polyreactive B cells that were preferentially selected to participate in B cell responses over time. Together, our data reveal polyreactivity is a beneficial feature of antibodies targeting conserved epitopes.

Keywords: Polyreactivity, broadly neutralizing antibodies, influenza viruses, monoclonal antibodies

Suggested Citation

Guthmiller, Jenna J. and Lan, Linda Yu-Ling and Fernández-Quintero, Monica and Han, Julianna and Bitar, Dalia and Hamel, Natalie J. and Stovicek, Olivia and Li, Le and Tepora, Micah and Henry, Carole and Neu, Karlynn E. and Dugan, Haley L. and Chen, Yao-Qing and Liu, Sean T. H. and Stamper, Christopher T. and Zheng, Nai-Ying and Huang, Min and Palm, Anna-Karin E. and García-Sastre, Adolfo and Nachbagauer, Raffael and Palese, Peter and Coughlan, Lynda and Krammer, Florian and Ward, Andrew B. and Liedl, Klaus R. and Wilson, Patrick C., Polyreactive Broadly Neutralizing B Cells are Selected to Provide Defense Against Pandemic Threat Influenza Viruses. Available at SSRN: https://ssrn.com/abstract=3624423 or http://dx.doi.org/10.2139/ssrn.3624423
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Jenna J. Guthmiller

University of Chicago - Department of Medicine

1101 East 58th Street
Chicago, IL 60637
United States

Linda Yu-Ling Lan

University of Chicago - Committee on Immunology

1101 East 58th Street
Chicago, IL 60637
United States

Monica Fernández-Quintero

The Scripps Research Institute - Center for Molecular Biosciences Innsbruck ( email )

La Jolla, CA 92037
United States

Julianna Han

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

Dalia Bitar

University of Chicago - Department of Medicine

5841 S Maryland Ave
Chicago, IL 60637
United States

Natalie J. Hamel

University of Chicago - Department of Medicine

5841 S Maryland Ave
Chicago, IL 60637
United States

Olivia Stovicek

University of Chicago - Department of Medicine

1101 East 58th Street
Chicago, IL 60637
United States

Le Li

University of Chicago - Department of Medicine

5841 S Maryland Ave
Chicago, IL 60637
United States

Micah Tepora

University of Chicago - Department of Medicine

5841 S Maryland Ave
Chicago, IL 60637
United States

Carole Henry

University of Chicago - Department of Medicine

1101 East 58th Street
Chicago, IL 60637
United States

Karlynn E. Neu

University of Chicago - Department of Medicine

5841 S Maryland Ave
Chicago, IL 60637
United States

Haley L. Dugan

University of Chicago - Committee on Immunology

Chicago, IL
United States

Yao-Qing Chen

University of Chicago - Department of Medicine

5841 S Maryland Ave
Chicago, IL 60637
United States

Sean T. H. Liu

Icahn School of Medicine at Mount Sinai - Department of Microbiology

United States

Christopher T. Stamper

University of Chicago - Committee on Immunology

Chicago, IL
United States

Nai-Ying Zheng

University of Chicago - Department of Medicine

1101 East 58th Street
Chicago, IL 60637
United States

Min Huang

University of Chicago - Department of Medicine

5841 S Maryland Ave
Chicago, IL 60637
United States

Anna-Karin E. Palm

University of Chicago - Department of Medicine

5841 S Maryland Ave
Chicago, IL 60637
United States

Adolfo García-Sastre

Icahn School of Medicine at Mount Sinai - Department of Microbiology

United States

Raffael Nachbagauer

Icahn School of Medicine at Mount Sinai - Department of Microbiology

United States

Peter Palese

Icahn School of Medicine at Mount Sinai - Department of Microbiology

United States

Lynda Coughlan

Icahn School of Medicine at Mount Sinai - Department of Microbiology

United States

Florian Krammer

Icahn School of Medicine at Mount Sinai - Department of Microbiology

United States

Andrew B. Ward

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

United States

Klaus R. Liedl

University of Innsbruck - Center for Molecular Biosciences Innsbruck

Universitätsstraße 15
Innsbruck, Innsbruck 6020
Austria

Patrick C. Wilson (Contact Author)

University of Chicago - Department of Medicine

5841 S Maryland Ave
Chicago, IL 60637
United States

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