Molecular insights into modulation of host innate immune response by viral proteins of RNA viruses SARS-CoV, HCV and Influenza virus

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dc.contributor.advisorErich Hoffmannen_US
dc.contributor.committeeMemberRuben Donisen_US
dc.contributor.committeeMemberJudith Aronsonen_US
dc.contributor.committeeMemberJoan Nicholsen_US
dc.contributor.committeeMemberJanice Endsleyen_US
dc.creatorSANTHANA GOWRI N/A THANGAVELU DEVARAJen_US
dc.date.accessioned2011-12-20T16:05:00Z
dc.date.accessioned2014-02-19T22:05:23Z
dc.date.available2010-09-28en_US
dc.date.available2011-12-20T16:05:00Z
dc.date.available2014-02-19T22:05:23Z
dc.date.created2009-07-20en_US
dc.date.issued2009-06-16en_US
dc.description.abstractOne of the first and fast line of defense launched by mammalian hosts to counter virus infection is production of type I interferon (IFN), an innate immune response that generates antiviral state to prevent virus replication and spread by expressing several IFN-stimulated genes. Type I interferon response depends on a set of germ-line encoded receptors called pattern recognition receptors (PRRs) that initiate antiviral signaling upon recognizing distinct pathogen associated molecular patterns (PAMPs). TLR3, RIG-I and MDA5, trigger complex intertwined signaling pathways in response to viral dsRNA leading to the activation of interferon regulatory transcription factors IRF3, IRF7 and NF-κB. These transcription factors mediate inflammatory process to clear virus infection. Viruses can evade host antiviral defenses by using several strategies. SARS coronavirus (SARS-CoV), a highly contagious causative agent of severe acute respiratory syndrome does not induce interferon response suggesting an unknown immune evasive mechanism. My experiments demonstrate that papain-like protease (PLpro) encoded by SARS-CoV is a potent interferon antagonist that functions independent of its protease activity. PLpro directly interacts with IRF-3 preventing its phosphorylation, dimerization, nuclear translocation and thus inhibits type I interferon response triggered by TLR3/RIG-I pathways. Hepatitis C virus is a major blood borne pathogen responsible for 100,000 deaths worldwide annually due to chronic liver cirrhosis. In cell culture normal human hepatocytes are not permissive to HCV replication due to intact TLR3/RIG-I/MDA5 antiviral signaling pathways. However, human hepatoma cells defective in antiviral signal pathways are found to permit HCV replication. My experiments involving reconstitution of functional TLR3 signaling pathways in human heptoma cells demonstrate that TLR3 plays a major role in HCV cellular permissiveness. Finally, my studies with influenza virus NS1 protein demonstrate that NS1 antagonizes the IFN response by blocking RIG-I activation in a strain specific manner. In conclusion, I have made an attempt to understand the complex antiviral signaling pathways at the cellular level in context to three distinct single strand RNA viruses namely, SARS-CoV, HCV and Influenza virus. Though, these viruses are detected by the same set of PRRs to trigger antiviral signaling, the mechanism by which they evade antiviral response appears to be distinct.en_US
dc.format.mediumelectronicen_US
dc.identifier.otheretd-07202009-200028en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/174
dc.language.isoengen_US
dc.rightsCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.en_US
dc.subjectviral proteins of SARS-CoVen_US
dc.subjectmodulation of hosten_US
dc.subjectinnate immune responseen_US
dc.subjectinfluenzaen_US
dc.subjectHCVen_US
dc.titleMolecular insights into modulation of host innate immune response by viral proteins of RNA viruses SARS-CoV, HCV and Influenza virusen_US
dc.type.genredissertationen_US
dc.type.materialtexten_US
thesis.degree.departmentN/Aen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhDen_US

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