Natural killer (NK) cells play an essential role in the defense against influenza virus, one of the deadliest respiratory viruses known today. The NKp46 receptor, expressed by NK cells, is critical for controlling influenza infections, as influenza-virus-infected cells are eliminated through the recognition of the viral hemagglutinin (HA) protein by NKp46. Here, we describe an immune-evasion mechanism of influenza viruses that is mediated by the neuraminidase (NA) protein. By using various NA blockers, we show that NA removes sialic acid residues from NKp46 and that this leads to reduced recognition of HA. Furthermore, we provide invivo and invitro evidence for the existence of this NA-mediated, NKp46-dependent immune-evasion mechanism and demonstrate that NA inhibitors, which are commonly used for the treatment of influenza infections, are useful not only as blockers of virus budding but also as boosters of NKp46 recognition.
Bibliographical noteFunding Information:
We thank J. Yewdell for kindly providing the anti-HA and anti-NA antibodies. This study was supported by a Croatia Israel Research Grant, a MOST-DKFZ Research Grant, an ICRF Professorship Grant, an ERC Advanced Grant, and grants from the Israeli Science Foundation, the Israeli ICORE, and the Association for International Cancer Research (all to O.M.). O.M. is a Crown Professor of Molecular Immunology.