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Title:Exploring the roles of key lipids in the influenza virus lifecycle
Author(s):Yeager, Ashley
Director of Research:Kraft, Mary L
Doctoral Committee Chair(s):Kraft, Mary L
Doctoral Committee Member(s):Harley, Brendan A; Leckband, Deborah E; Shisler, Joanna L
Department / Program:Chemical & Biomolecular Engr
Discipline:Chemical Engineering
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):influenza virus
sphingolipids
cholesterol
lipid rafts
plasma membrane
high-resolution secondary ion mass spectrometry
isotope-labeling
3-dimensional (3D) imaging
ceramide
neutral sphingomyelinase
Abstract:The influenza virus is a common respiratory pathogen with the capacity to cause global pandemics affecting millions of people, contributing substantially to overall mortality and morbidity. Thus, considerable research focuses on the prevention and treatment of influenza virus infection. Despite the availability of vaccines, influenza infection continues to be a common illness due to its ability to rapidly mutate and reassort, introducing novel strains. Focusing on host factors that are exploited by the virus could lead to the development of new therapeutics with lower potential for drug resistance and confer universal strain potency. Sphingolipids are a host lipid that is a known influenza target. According to a long-standing hypothesis, cholesterol and sphingolipids form distinct plasma membrane domains, termed lipid rafts, that help recruit newly synthesized influenza components to virus assembly sites for progeny budding. However, the sphingolipid and cholesterol abundance at this bud zone remains a mystery due to the limited means to image these lipids in the plasma membrane without using labels that may alter their distributions or functions. Recently, a high-resolution secondary ion mass spectrometry approach was used to image stable isotope-labeled cholesterol and sphingolipids in the plasma membranes of fibroblast cells with sub-100 nm lateral resolution. These reports established that sphingolipid domains do not have elevated cholesterol levels, calling into question this hypothesis. We use this technique to show for the first time that the influenza virus does not bud from sphingolipid-enriched domains in the plasma membranes of whole cells. Further experiments also revealed the intracellular 3-dimensional distributions of cholesterol and sphingolipids within a cell with high resolution. This new imaging capability will expand our knowledge of the intricate network of these lipids and help shape our understanding of their exploitation during infection. Sphingolipids are key influenza targets, however, this research indicates that they are not targeted at the plasma membrane, specifically, to recruit viral components for budding. We also discuss the role of ceramide, a central sphingolipid in the sphingolipid biosynthesis pathway, in the influenza lifecycle. Our analyses indicate the need for further studies on ceramide as a potential target of the influenza virus through its regulatory enzymes.
Issue Date:2016-07-13
Type:Thesis
URI:http://hdl.handle.net/2142/92947
Rights Information:Copyright 2016 Ashley N. Yeager
Date Available in IDEALS:2016-11-10
Date Deposited:2016-08


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