Evasion of RIG-I/MDA5 and TLR3-mediated innate immunity by hepatitis A virus

dc.contributor.advisorStanley M. Lemonen_US
dc.contributor.committeeMemberSteven A. Weinmanen_US
dc.contributor.committeeMemberShinji Makinoen_US
dc.contributor.committeeMemberRobert A. Daveyen_US
dc.contributor.committeeMemberRichard E. Lloyden_US
dc.creatorLin Quen_US
dc.date.accessioned2011-12-20T16:05:03Z
dc.date.accessioned2014-02-19T22:05:24Z
dc.date.available2010-09-28en_US
dc.date.available2011-12-20T16:05:03Z
dc.date.available2014-02-19T22:05:24Z
dc.date.created2010-07-21en_US
dc.date.issued2010-06-18en_US
dc.description.abstractSince the identification of several families of pattern recognition receptors (PRRs), their roles in the innate immune system and how they are regulated by the invading pathogens have been the subjects of extensive research. Cellular helicases RIG-I and MDA5, and Toll-like receptor 3 (TLR3) are PRRs that detect virus-specific double stranded RNA (dsRNA). Activation of these PRRs by dsRNA lead to their interaction with adaptor proteins, which engage downstream kinases to activate two critical transcription factors, NF-kB and IRF3, in the induction of type I interferons (IFNs) and IFN-stimulated genes (ISGs) that ultimately establish an antiviral state. These signaling pathways are central to host antiviral defense and thus become targets for viral interference. Hepatitis A virus (HAV), a hepatotropic picornavirus, is capable of blocking IRF3 activation and type I IFN expression in cell culture, but the exact mechanism(s) remains undefined. Our studies revealed that HAV disrupts RIG-I/MDA5-mediated induction of type I IFN through proteolysis of MAVS, a mitochondrial-localized adaptor of RIG-I and MDA5, by the viral 3ABC protease precursor. The 3ABC cleavage of MAVS requires both the protease activity of 3Cpro and a transmembrane domain in 3A that directs 3ABC to mitochondria. The signaling ability of MAVS depends on its mitochondrial localization; cleavage of MAVS by 3ABC removes MAVS from mitochondia, thus abolishing its adaptor function. We also demonstrated that the parallel, yet independent, TLR3 signaling pathway is also inhibited by HAV through cleavage of the adaptor protein TRIF by the 3CD protease-polymerase precursor. Cleavage of TRIF by 3CD requires both the protease activity of 3Cpro and the 3Dpol moiety, but not the 3Dpol polymerase activity, in an “in cis” manner. This research also revealed a unique order of processing in the 3CD cleavage of TRIF, and an unexpected role of the 3Dpol domain in modulating the substrate specificity of 3CD that allows it to cleave non-canonical 3Cpro cleavage sites within TRIF. The data generated in this dissertation provide two major mechanisms by which HAV evades innate immune responses, and extend our understanding of the signaling pathways of the innate immune system.en_US
dc.format.mediumelectronicen_US
dc.identifier.otheretd-07212010-120750en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/179
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.subjectIPS-1 Cardif TICAM-1 Picornavirusen_US
dc.titleEvasion of RIG-I/MDA5 and TLR3-mediated innate immunity by hepatitis A virusen_US
dc.type.genredissertationen_US
dc.type.materialtexten_US
thesis.degree.departmentMicrobiology and Immunologyen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhDen_US

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