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

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

Significant effects of different Sia modifications on the binding of pathogens or the activities of their sialidases (neuraminidases) have been suggested, but in general these are still 120 not well understood. Influenza A viruses (IAV) use Sia as primary receptors for host recognition and cell entry through the activity of two surface glycoproteins that interact with Sia, hemagglutinin (HA) and neuraminidase (NA). HA is a trimeric protein that binds Sia to initiate the endocytic uptake of the virus by the cell, leading to fusion between the viral envelope and the endosomal membrane after exposure of the virus to low pH (36) . NA is a sialidase which 125 cleaves Sia from the mucus, cell surface, and from viral glycoproteins, allowing the virus to penetrate through mucus to the epithelial cells and reducing the aggregation of virions after budding from the surface of cells (37). Previous studies have suggested that 7,9-O-and 9-O-Ac Sia are expressed on cells or in tissues of many IAV host species and there is some evidence that these modifications may be inhibitory for NA activity and HA binding (38, 39) . However, the 130 specific effects of 7,9-O-and 9-O-Ac on the binding of Sia by HA or the cleavage of Sia by IAV NA have not been examined in detail, and it is unclear whether these changes influence All rights reserved. No reuse allowed without permission.