Ferrets exclusively synthesize Neu5Ac and express naturally humanized influenza A virus receptors

• Published in: Nature communications 2014-12, Vol.5 (1), p.5750-5750, Article 5750
• Main Authors: Ng, Preston S.K., Böhm, Raphael, Hartley-Tassell, Lauren E., Steen, Jason A., Wang, Hui, Lukowski, Samuel W., Hawthorne, Paula L., Trezise, Ann E.O., Coloe, Peter J., Grimmond, Sean M., Haselhorst, Thomas, von Itzstein, Mark, Paton, Adrienne W., Paton, James C., Jennings, Michael P.
• Format: Article
• Language: English
• Subjects: 631/208; 692/699/255/2514; Animals; Base Sequence; Caniformia - genetics; Caniformia - immunology; Caniformia - virology; Carbohydrate Sequence; Exons; Ferrets - genetics; Ferrets - immunology; Ferrets - virology; Gene Expression; Humanities and Social Sciences; Humans; Influenza A virus - genetics; Influenza A virus - metabolism; Mixed Function Oxygenases - chemistry; Mixed Function Oxygenases - deficiency; Mixed Function Oxygenases - genetics; Molecular Sequence Data; multidisciplinary; N-Acetylneuraminic Acid - chemistry; N-Acetylneuraminic Acid - metabolism; Neuraminic Acids - chemistry; Neuraminic Acids - metabolism; Orthomyxoviridae Infections - virology; Receptors, Virus - chemistry; Receptors, Virus - genetics; Receptors, Virus - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Sequence Deletion; Viral Tropism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6750

Mammals express the sialic acids N -acetylneuraminic acid (Neu5Ac) and N- glycolylneuraminic acid (Neu5Gc) on cell surfaces, where they act as receptors for pathogens, including influenza A virus (IAV). Neu5Gc is synthesized from Neu5Ac by the enzyme cytidine monophosphate- N -acetylneuraminic acid hydroxylase (CMAH). In humans, this enzyme is inactive and only Neu5Ac is produced. Ferrets are susceptible to human-adapted IAV strains and have been the dominant animal model for IAV studies. Here we show that ferrets, like humans, do not synthesize Neu5Gc. Genomic analysis reveals an ancient, nine-exon deletion in the ferret CMAH gene that is shared by the Pinnipedia and Musteloidia members of the Carnivora. Interactions between two human strains of IAV with the sialyllactose receptor (sialic acid—α2,6Gal) confirm that the type of terminal sialic acid contributes significantly to IAV receptor specificity. Our results indicate that exclusive expression of Neu5Ac contributes to the susceptibility of ferrets to human-adapted IAV strains. Ferrets constitute a useful model for influenza research because they are susceptible to human-adapted flu viruses. Here, the authors show that ferrets, like humans, lack a functional CMAH enzyme and synthesize a single type of sialic acid (Neu5Ac), resulting in naturally humanized influenza virus receptors.