Understanding Host Antiviral Signaling Pathways

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Understanding Host Antiviral Signaling Pathways

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dc.contributor.advisor Chen, Zhijian J. en
dc.creator Bhargava, Rashu en
dc.date.accessioned 2010-07-12T18:33:04Z en
dc.date.available 2010-07-12T18:33:04Z en
dc.date.issued 2006-09-25 en
dc.identifier.other 182546815 en
dc.identifier.uri http://hdl.handle.net/2152.5/596 en
dc.description.abstract The innate immune response is the first line of defense against viral infections. Recent studies have revealed two immune receptor systems that detect virally-derived nucleic acids and trigger signaling pathways which lead to the activation of transcription factors like nuclear factor-kappa B (NF-kappa B), interferon regulatory factor 3 (IRF3) and interferon regulatory factor 7 (IRF7). These transcription factors regulate the synthesis of protective cytokines including type I interferons. The first detection system includes members of the toll-like receptor family (TLR3, TLR7, TLR8 and TLR9) that reside in the endosome and signal through the associated adaptor proteins. The second pathway uses retinoic acid inducible gene - I (RIG-I) to detect cytosolic viral double-stranded RNA. RIG-I signals to NF-kappa B and IRFs through its N-terminal CARD domains. An important area of research is to identify the downstream host factors that participate in these pathways and to determine the mechanism by which they function. Here, I describe the development of an in vitro biochemical assay to detect the activation of a key kinase involved in the activation of IRF3. This assay will be a valuable tool for identifying not only the specific IRF3 kinase, but also other molecular components involved in the antiviral signaling pathway. A bioinformatics approach led to the identification of a CARD domain containing protein, termed MAVS (Mitochondrial AntiViral Signaling protein) that functions downstream of RIG-I in the antiviral signaling pathway. Besides the N-terminal CARD domain, MAVS also contains a hydrophobic C-terminal transmembrane domain that targets the protein to the outer membrane of the mitochondria. The mitochondrial localization of MAVS is essential for signaling by MAVS. The importance of mitochondrial localization of MAVS for its function is underscored by the finding that hepatitis C virus (HCV) shuts down the host innate immune system by cleaving MAVS off the mitochondria. HCV achieves this through the action of NS3/4A, a virally encoded serine protease, which cleaves MAVS before the transmembrane domain at Cys-508. Prior to the identification of MAVS, the focus of antiviral research was on understanding the regulation of key transcription factors by established cytosolic signaling cascades. Our findings have established an important role for mitochondria in regulating antiviral immunity and represent a new paradigm in understanding the host-pathogen relationship. en
dc.format.medium Electronic en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.subject CARD Signaling Adaptor Proteins en
dc.subject Interferon Regulatory Factor-3 en
dc.subject Mitochondria en
dc.title Understanding Host Antiviral Signaling Pathways en
dc.type.material Text en
dc.type.genre dissertation en
dc.format.digitalOrigin born digital en
thesis.degree.grantor Graduate School of Biomedical Sciences en
thesis.degree.department en
thesis.degree.name Doctor of Philosophy en
thesis.degree.level Ph.D. en
thesis.degree.discipline Cell Regulation en
thesis.date.available 2006-11-27 en

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