Abstract
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.
Highlights
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)
We developed the hypothesis that a contributing factor to the susceptibility of ferrets to human strains of IAV may be the type of sialic acid they express
Our study reveals that ferrets are a naturally humanized model system with respect to IAV receptor biology
Summary
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). HA is responsible for the initial attachment of the virus to the host cell membrane by binding to sialic-acid (SA) receptors, while NA ensures mobility of virus in the respiratory tract and release of new viral progeny by its sialic-acid cleavage activity[2] Sequence variations in these proteins may alter IAV host range and virulence by changing their specificity for the spectrum of distinct HA3 receptor structures and NA substrates[4] on the cells, tissues and organs of vertebrate hosts. This continual and rapid IAV evolution results in the emergence of new strains from animal reservoirs to infect humans; the lack of protective immunity from previous IAV infections; the requirement for regular reformulation of IAV vaccines; and the generation of IAV resistance to anti-viral drugs[5]. Analyses of whole human IAV with fully characterized IAV receptor structures confirm the importance of Neu5Ac in both HA and NA functions, and that exclusive expression of Neu5Ac is a contributing factor to the unique suitability of ferrets as a model for human-adapted IAV
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