N-Glycolylneuraminic Acid as a Receptor for Influenza A Viruses

Abstract

Summary: 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. : Broszeit and colleagues demonstrate that influenza A viruses recognize either N-acetyl or N-glycolyl neuraminic acid, and they explain these specificities using X-ray structures. NeuGc-binding viruses are perfectly viable, and neuraminidases can cleave NeuGc-containing receptor structures. There is an apparent selection now for NeuAc, as no known NeuGc-binding virus currently circulates. Keywords: influenza A virus, receptor-binding, sialic acid, glycan-array, hemagglutinin, neuraminidase, crystal structure