Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies

Ivan Kosik, Davide Angeletti, James S. Gibbs, Matthew Angel, Kazuyo Takeda, Martina Kosikova, Vinod Nair, Heather D. Hickman, Hang Xie, Christopher B. Brooke, Jonathan W. Yewdell

Research output: Contribution to journalArticle

Abstract

Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase (NA) activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza-infected mice, likely due at least in part to NA-mediated inhibition of FcγR-dependent activation of innate immune cells by Ab bound to virions. Food and Drug Administration–approved NA inhibitors enhance anti-stem–based Fc-dependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.

Original languageEnglish (US)
Pages (from-to)304-316
Number of pages13
JournalJournal of Experimental Medicine
Volume216
Issue number2
DOIs
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Kosik, I., Angeletti, D., Gibbs, J. S., Angel, M., Takeda, K., Kosikova, M., Nair, V., Hickman, H. D., Xie, H., Brooke, C. B., & Yewdell, J. W. (2019). Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies. Journal of Experimental Medicine, 216(2), 304-316. https://doi.org/10.1084/jem.20181624