INFLUENZA VIRUS INTERACTIONS WITH MODIFIED SIALIC ACIDS
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Influenza A viruses (IAV) are an important human pathogen causing 3 to 5 million cases of severe illness and 290,000 to 650,000 deaths globally each year (WHO, 2018). IAVs have broad host ranges and are able to infect a wide array of animal species including humans, pigs, horses, dogs, waterfowl, and domestic poultry. IAV use sialic acids (Sia) as the primary receptor for infection via the hemagglutinin (HA) and neuraminidase (NA) glycoproteins. Sia are found in large amounts both on the cell surface as part of the glycocalyx and in mucus that protects the respiratory and gastrointestinal tracts. Sia may be chemically modified (including 7,9-O-, 9-O-acetyl, 5-N-glycolyl) and are attached to glycan chains through different linkages, which vary between hosts and tissues. While the importance of Sia α2,3- and α2,6-linkages to IAV tropism and evolution have been well studied, the roles of modified Sia in IAV host adaptation are not well known. Modified Sia have been identified as inhibitors of NA and HA, but their role during infection is unclear. This dissertation discusses the regulation of 7,9-O- and 9-O-acetyl modifications in cells through the action of the sialate 7,9-O-acetyltransferase, CasD1, and its complementary enzyme the sialate 7,9-O-acetylesterase, SIAE. Additionally, the distribution of 7,9-O-, 9-O-, and 4-O-acetyl, along with 5-N-glycolyl, modified Sia is examined for different mouse tissues, and secreted mucus and erythrocytes from IAV host species. The effects of these modifications on IAV HA and NA function is also determined, as well as their effect on virus infection. Finally, the outcome of passaging three IAV virus strains on different MDCK cell lineages, including those expressing different modified Sia, was examine using deep sequencing to determine changes in viral populations over time. This dissertation provides new information on the role of chemically modified Sia on IAV virus:host interactions, which had previously been overlooked in the IAV research field. Understanding the roles of modified Sia will give a more complete understanding of the interactions of these viruses with this complex carbohydrate receptor as they move between hosts, thus better informing our knowledge of IAV evolution and emergence.
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evolution; influenza; modifications; Sialic acids
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Parrish, Colin R
Russell, David G.
Russell, David G.
Biomedical and Biological Sciences
Ph. D., Biomedical and Biological Sciences
Doctor of Philosophy
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Attribution-NoDerivatives 4.0 International
dissertation or thesis