Neuraminidase-mediated, NKp46-dependent immune-evasion mechanism of influenza viruses

Yotam Bar-On; Ariella Glasner; Tal Meningher; Hagit Achdout; Chamutal Gur; Dikla Lankry; Alon Vitenshtein; Adrienne F A Meyers; Michal Mandelboim; Ofer Mandelboim

doi:10.1016/j.celrep.2013.03.034

Neuraminidase-mediated, NKp46-dependent immune-evasion mechanism of influenza viruses

Cell Rep. 2013 Apr 25;3(4):1044-50. doi: 10.1016/j.celrep.2013.03.034. Epub 2013 Apr 18.

Authors

Yotam Bar-On¹, Ariella Glasner¹, Tal Meningher^{2

3}, Hagit Achdout^{1

4}, Chamutal Gur¹, Dikla Lankry¹, Alon Vitenshtein¹, Adrienne F A Meyers^{5

6}, Michal Mandelboim^#², Ofer Mandelboim^#¹

Affiliations

¹ The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.
² Central Virology Laboratory, Ministry of Health, Public Health Services, Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan 52662, Israel.
³ The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
⁴ Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
⁵ National Laboratory for HIV Immunology, National HIV and Retrovirology Laboratories, Public Health Agency of Canada, Winnipeg R3E 3R2, Canada.
⁶ Department of Medical Microbiology, University of Manitoba, Winnipeg R3E 0J9, Canada.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Ly / genetics
Antigens, Ly / metabolism
Cell Line, Tumor
Enzyme Inhibitors / pharmacology
Hemagglutinin Glycoproteins, Influenza Virus / metabolism
Humans
Immune Evasion / drug effects
Influenza A Virus, H1N1 Subtype / enzymology
Influenza A Virus, H1N1 Subtype / physiology
Influenza A Virus, H3N2 Subtype / enzymology
Influenza A Virus, H3N2 Subtype / physiology
Killer Cells, Natural / immunology
Killer Cells, Natural / metabolism
Mice
Mice, Knockout
Natural Cytotoxicity Triggering Receptor 1 / deficiency
Natural Cytotoxicity Triggering Receptor 1 / genetics
Natural Cytotoxicity Triggering Receptor 1 / metabolism*
Neuraminidase / antagonists & inhibitors
Neuraminidase / metabolism*
Orthomyxoviridae / enzymology*
Orthomyxoviridae / physiology
Oseltamivir / pharmacology

Substances

Antigens, Ly
Enzyme Inhibitors
Hemagglutinin Glycoproteins, Influenza Virus
Natural Cytotoxicity Triggering Receptor 1
Ncr1 protein, mouse
Oseltamivir
Neuraminidase

Grants and funding

320473/ERC_/European Research Council/International