STRUCTURAL CHARACTERIZATION OF MUCINS

Scripps Research Institute, The, La Jolla CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Influenza virions target their hosts by first binding to nine-carbon backbone sugars (sialic acids, Sias) on host cells to initiate infection. After binding sialylated structures on the cell membrane, influenza viruses infect cells via endocytic pathways. The two major viral envelope proteins are hemagglutinin (HA), which binds to Sias, and neuraminidase (NA), which cleaves host Sias. All Influenza A virus subtypes have been isolated from wild bird species, which are considered the reservoir for infection. Influenza targets and binds sialylated glycans on the gastrointestinal (GI) tract and respiratory epithelia. The epithelium is covered with a thick mucus layer comprised of sialylated secreted-mucins, which can potentially act as a natural barrier for influenza infection by providing a "decoy" for viruses HA binding. Mucins are complex and heavily glycosylated O-linked glycoproteins, which form the major component of the mucus layer. Binding to mucins will inhibit influenza viruses from reaching the underlying epithelial cells, however, influenza NA can potentially cleave the sialylated mucins and allow virus penetration toward the host cell. The relationship between mucin-binding by the viruses HA and cleaving by the viruses NA will determine whether the viruses will be able to escape from the "decoy". Despite the substantial thickness of the mucin layer (10-200 [unreadable]m), and the potential role of mucins in influenza binding and infection, studies of influenza host tissues interactions are done on dehydrated tissues in which the mucus layer is destroyed. We propose to study the interplay between influenza virus and the secreted mucus, and to obtain molecular resolution information on influenza-mucin interaction, by cryo-electron microscopy.