TY - JOUR
T1 - Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies
AU - Kosik, Ivan
AU - Angeletti, Davide
AU - Gibbs, James S.
AU - Angel, Matthew
AU - Takeda, Kazuyo
AU - Kosikova, Martina
AU - Nair, Vinod
AU - Hickman, Heather D.
AU - Xie, Hang
AU - Brooke, Christopher B.
AU - Yewdell, Jonathan W.
N1 - Publisher Copyright:
© 2018 Zheng and Cantley
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20181624
DO - 10.1084/jem.20181624
M3 - Article
C2 - 30683737
AN - SCOPUS:85061148603
SN - 0022-1007
VL - 216
SP - 304
EP - 316
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -