N-Glycolylneuraminic Acid as a Receptor for Influenza A Viruses

Cell Rep. 2019 Jun 11;27(11):3284-3294.e6. doi: 10.1016/j.celrep.2019.05.048.


A species barrier for the influenza A virus is the differential expression of sialic acid, which can either be α2,3-linked for avians or α2,6-linked for human viruses. The influenza A virus hosts also express other species-specific sialic acid derivatives. One major modification at C-5 is N-glycolyl (NeuGc), instead of N-acetyl (NeuAc). N-glycolyl is mammalian specific and expressed in pigs and horses, but not in humans, ferrets, seals, or dogs. Hemagglutinin (HA) adaptation to either N-acetyl or N-glycolyl is analyzed on a sialoside microarray containing both α2,3- and α2,6-linkage modifications on biologically relevant N-glycans. Binding studies reveal that avian, human, and equine HAs bind either N-glycolyl or N-acetyl. Structural data on N-glycolyl binding HA proteins of both H5 and H7 origin describe this specificity. Neuraminidases can cleave N-glycolyl efficiently, and tissue-binding studies reveal strict species specificity. The exclusive manner in which influenza A viruses differentiate between N-glycolyl and N-acetyl is indicative of selection.

Keywords: crystal structure; glycan-array; hemagglutinin; influenza A virus; neuraminidase; receptor-binding; sialic acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Chickens
  • Dogs
  • Erythrocytes / metabolism
  • Erythrocytes / virology
  • Hemagglutinins / chemistry
  • Hemagglutinins / metabolism
  • Horses
  • Host Specificity*
  • Influenza A virus / metabolism*
  • Influenza A virus / pathogenicity
  • Neuraminic Acids / chemistry
  • Neuraminic Acids / metabolism*
  • Orthomyxoviridae Infections / metabolism*
  • Orthomyxoviridae Infections / veterinary
  • Protein Binding


  • Hemagglutinins
  • Neuraminic Acids
  • N-glycolylneuraminic acid