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  3. Outwhitting influenza : permissive mutations may compensate for fitness defects of the influenza drug-resistance mutation via multiple mechanisms
Title

Outwhitting influenza : permissive mutations may compensate for fitness defects of the influenza drug-resistance mutation via multiple mechanisms

    Item Description
    Limited Access
    The author(s) chose to restrict access to this thesis to current Whitman students, faculty, and staff. Please log in to view it.
    Linked Agent
    Creator (cre): Wanke, Kristen McKenzie
    Advisor (adv): Russo, Jim
    Department (dpt): Whitman College. Biochemistry, Biophysics and Molecular Biology
    Date
    May 20, 2020
    Graduation Year
    2020
    Abstract

    Neuraminidase (NA), a surface glycoprotein enzyme on influenza virus, is the target of the most commonly used influenza antiviral, oseltamivir. The H274Y mutation in NA confers resistance to oseltamivir; however, this mutation also decreases viral fitness and NA expression on the cell surface. Permissive mutations buffer the deleteriousness of H274Y by rescuing NA cell surface expression, viral growth in tissue culture, and ferret transmission. These permissive mutations enabled the fixation of H274Y in circulating H1N1 influenza viruses prior to the replacement of this clade with oseltamivir-sensitive (H274) "swine flu” pandemic H1N1 in 2009. Interestingly, several of these have fixed in the oseltamivir-sensitive pandemic H1N1 lineage since 2009, which may make it possible for oseltamivir resistance to emerge in the future on a global scale. We hypothesized that the permissive mutations may buffer the effects of H274Y by increasing the melting temperature (Tm) of NA. To test this, we measured the Tm of wild type (WT) NA, H274Y, three permissive mutations, and the H274Y + permissive double mutants. We conclude that while some permissive mutations increase the Tm of NA, others may counteract the effects of H274Y through an alternative mechanism.

    Subject
    Influenza
    Drug resistance
    Mutation (Biology)
    Neuraminidase
    Oseltamivir
    Viruses -- Evolution
    Orthomyxoviruses
    Immunity
    Science
    Academic theses
    Whitman College 2020 -- Dissertation collection -- Biochemistry, Biophysics, and Molecular Biology
    Genre
    Theses
    Extent
    24 pages
    Permanent URL
    http://works.whitman.edu/2020089
    Rights
    http://rightsstatements.org/vocab/InC/1.0/
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    THESIS_ 2020_1158575538_001
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