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dc.contributor.advisorAllen, Todd M.
dc.contributor.authorChiang, Jessica
dc.date.accessioned2019-05-16T10:55:20Z
dc.date.created2018-03
dc.date.issued2018-01-16
dc.date.submitted2018
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:39945342*
dc.description.abstractThe cytosolic innate immune receptor retinoic acid-inducible gene-I (RIG-I) recognizes double-stranded RNA (dsRNA) that emerges during viral infection and initiates an antiviral response comprised of interferon (IFN) and proinflammatory cytokine induction. Although RIG-I plays a role in the immune response to DNA viruses such as herpes simplex virus 1 (HSV-1), little is known about the nature of RNA ligands that activate RIG-I during DNA virus infection, and moreover, how these viruses antagonize RIG-I signaling. To identify physiological RNA ligands of RIG-I during HSV-1 infection, we performed RNA-Seq on RIG-I-bound RNA from HSV-1-infected cells and found that the 5S rRNA pseudogene RNA5SP141 was highly enriched with RIG-I specifically in infected cells and elicited a robust RIG-I-dependent antiviral response. In uninfected cells, RNA5SP141 is found primarily in the nucleus, but upon HSV-1 infection, its localization becomes predominantly cytoplasmic. Furthermore, HSV-1-induced shutoff of host protein expression results in the downregulation of proteins that normally interact with and shield RNA5SP141 from RIG-I detection. Depletion of endogenous RNA5SP141 strongly dampened the antiviral response to HSV-1 and the related Epstein-Barr virus, as well as influenza A virus, an RNA virus. Taken together, our data show that viral infection can lead to deshielding of endogenous RNAs that activate innate immunity. The innate immune system is tightly regulated by a variety of regulatory mechanisms that prevent aberrant signaling. However, these pathways can be exploited by viruses to suppress antiviral signaling during infection. Here we show that the serine/threonine kinase US3 of HSV-1 suppresses RIG-I-mediated signaling by phosphorylating a regulatory residue in the RIG-I signaling domain. A recombinant HSV-1 encoding catalytically-inactive US3 was unable to phosphorylate RIG-I and elicited higher levels of IFNs and proinflammatory cytokines compared to wild-type (WT) HSV-1. In summary, these studies have uncovered both a novel host mechanism for detecting DNA virus infection by sensing ‘exposed’ endogenous RNAs and a viral mechanism that co-opts a host regulatory pathway to suppress antiviral signaling. Our findings provide insight into the molecular details governing innate immunity and illustrate the complex interconnectedness of virus and host.
dc.description.sponsorshipMedical Sciences
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectBiology, Virology
dc.subjectBiology, Cell
dc.subjectBiology, Molecular
dc.titleActivation and Antagonism of RIG-I-Mediated Innate Immune Signaling by Herpes Simplex Virus 1
dc.typeThesis or Dissertation
dash.depositing.authorChiang, Jessica
dc.date.available2019-05-16T10:55:20Z
thesis.degree.date2018
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberGehrke, Lee
dc.contributor.committeeMemberRabkin, Samuel D.
dc.contributor.committeeMemberFitzgerald, Katherine A.
dc.type.materialtext
thesis.degree.departmentMedical Sciences
dash.identifier.vireohttp://etds.lib.harvard.edu/gsas/admin/view/1934
dc.description.keywordsinnate immunity; pattern-recognition receptors; RIG-I; herpes simplex virus; pseudogenes; pathogen-associated molecular patterns
dc.identifier.orcid0000-0002-6987-8693
dash.author.emailjjchiang@gmail.com


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