Neuraminidase-Mediated, NKp46-Dependent Immune-Evasion Mechanism of Influenza Viruses

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 in vivo and in vitro 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. [Display omitted] •Influenza viruses use their NA proteins to escape NK cell killing•NA impairs the NKp46 recognition of influenza viruses•The impairment of NKp46 recognition reduces virus elimination in vitro and in vivo•NA inhibitors boost NKp46 recognition Natural killer (NK) cells eliminate influenza-virus-infected cells via recognition of the viral hemagglutinin protein by the NK receptor NKp46. Mandelboim and colleagues demonstrate in vitro and in vivo that influenza viruses counter this recognition by using their viral neuraminidase (NA) protein. They also show that NA inhibitors that are widely used for the treatment of influenza virus infections boost the NKp46-mediated elimination of influenza-virus-infected cells.