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The effects of modified sialic acids on mucus and erythrocytes on influenza A virus HA and NA functions

By Karen N. Barnard, Brynn K Alford-Lawrence, David W Buchholz, Brian R. Wasik, Justin R LaClair, Hai Yu, Rebekah Honce, Stefan Ruhl, Petar Pajic, Erin K Daugherity, Xi Chen, Stacey L. Schultz-Cherry, Hector C. Aguilar, Ajit Varki, Colin R. Parrish

Posted 10 Oct 2019
bioRxiv DOI: 10.1101/800300

Sialic acids (Sia) are the primary receptors for influenza viruses, and are widely displayed on cell surfaces and in secreted mucus. Sia may be present in variant forms that include O -acetyl modifications at C4, C7, C8, and C9 positions, and N-acetyl or N-glycolyl at C5. They can also vary in their linkages, including a2-3 or a2-6-linkages. Here, we analyzed the distribution of modified Sia in cells and tissues of wild-type mice, or in mice lacking cytidine 5'-monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) enzyme that synthesizes N-glycolyl modifications (Neu5Gc). We also examined the variation of Sia forms on erythrocytes and saliva from different animals. To determine the effect of Sia modifications on influenza A virus (IAV) infection, we tested for effects on hemagglutinin (HA) binding and neuraminidase (NA) cleavage. We confirmed that 9- O -acetyl, 7,9- O -acetyl, 4- O -acetyl, and Neu5Gc modifications are widely but variably expressed in mouse tissues, with the highest levels detected in the respiratory and gastrointestinal tracts. Secreted mucins in saliva and surface proteins of erythrocytes showed a great degree of variability in display of modified Sia between different species. IAV HA from different virus strains showed consistently reduced binding to both Neu5Gc and O-acetyl modified Sia; however, while IAV NA were inhibited by Neu5Gc and O -acetyl modifications, there was significant variability between NA types. The modifications of Sia in mucus may therefore have potent effects on the functions of IAV, and may affect both pathogens and the normal flora of different mucosal sites.

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