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dc.contributor.advisorGehrke, Leeen_US
dc.contributor.authorChan, Ying Kaien_US
dc.date.accessioned2015-07-17T17:41:18Z
dash.embargo.terms2017-05-01en_US
dc.date.created2015-05en_US
dc.date.issued2015-05-07en_US
dc.date.submitted2015en_US
dc.identifier.citationChan, Ying Kai. 2015. Interplay of Dengue Virus and the Human Immune Response. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17467339
dc.description.abstractRIG-I is a key cytosolic sensor of many RNA viruses, including dengue virus (DV), the most significant arboviral pathogen. Upon viral RNA binding, RIG-I signals via the adaptor protein MAVS, located at mitochondria, to induce the expression of interferons (IFNs), proinflammatory cytokines and interferon-stimulated genes (ISGs), thereby establishing an antiviral state. Among the ISGs, the IFITM proteins are critical for antiviral restriction of numerous pathogenic viruses including DV by inhibiting viral entry. Here, we uncover how DV escapes RIG-I-mediated immunity. The NS3 protein of DV binds directly to 14-3-3ε, a mitochondrial-targeting protein that is essential for translocation of RIG-I from the cytosol to mitochondria. Specifically, NS3 blocks 14-3-3ε from forming a “translocon” complex with RIG-I and its upstream activator, TRIM25, thereby inhibiting RIG-I translocation to mitochondria for MAVS interaction and antiviral signaling. Furthermore, RIG-I that fails to translocate to mitochondria is degraded in a lysosome-dependent manner in DV- infected cells. Intriguingly, NS3 binds to 14-3-3ε using a phosphomimetic motif that resembles a canonical phospho-serine/threonine motif found in cellular 14-3-3-interaction partners. We engineer a recombinant DV encoding a mutant NS3 protein deficient in 14-3-3ε binding (DV2KIKP) and find that this mutant virus is attenuated in replication compared to the parental virus. Strikingly, DV2KIKP fails to antagonize RIG-I and elicits high levels of IFNs, proinflammatory cytokines and ISGs in human hepatocytes and monocytes. Taken together, our data reveal a novel phosphomimetic-based mechanism for viral antagonism of innate immunity and provide a foundation for DV vaccine development. DV can infect cells directly, or complex with non-neutralizing antibodies to infect Fc- receptor-bearing cells in a secondary infection, which is associated with severe disease. While it has been shown that IFITMs restrict DV direct infection, it is unknown if the latter process, commonly termed antibody-dependent enhancement (ADE), might bypass IFITM-mediated restriction. Comparison of direct and ADE-mediated DV infection shows that IFITM proteins restrict both infection modes equally, suggesting that upregulation of IFITMs may be a therapeutic strategy. In summary, our work elucidates several molecular aspects of the interplay of DV with the human immune response, which may guide the rational design of vaccines and antivirals.en_US
dc.description.sponsorshipMedical Sciencesen_US
dc.format.mimetypeapplication/pdfen_US
dc.language.isoenen_US
dash.licenseLAAen_US
dc.subjectBiology, Virologyen_US
dc.subjectHealth Sciences, Immunologyen_US
dc.subjectBiology, Microbiologyen_US
dc.titleInterplay of Dengue Virus and the Human Immune Responseen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorChan, Ying Kaien_US
dc.date.available2017-05-01T07:31:23Z
thesis.degree.date2015en_US
thesis.degree.grantorGraduate School of Arts & Sciencesen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
dc.contributor.committeeMemberCepko, Constanceen_US
dc.contributor.committeeMemberRabkin, Samuelen_US
dc.contributor.committeeMemberMuhlberger, Elkeen_US
dc.type.materialtexten_US
thesis.degree.departmentMedical Sciencesen_US
dash.identifier.vireohttp://etds.lib.harvard.edu/gsas/admin/view/288en_US
dc.description.keywordsdengue; innate immunityen_US
dash.author.emailchan_yingkai@yahoo.com.sgen_US
dash.identifier.drsurn-3:HUL.DRS.OBJECT:25164697en_US
dash.contributor.affiliatedChan, Ying Kai


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