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dc.contributor.advisorStetson, Daniel B.en_US
dc.contributor.authorEckard, Sterling Clayen_US
dc.date.accessioned2014-10-13T16:56:07Z
dc.date.submitted2014en_US
dc.identifier.otherEckard_washington_0250E_13747.pdfen_US
dc.identifier.urihttp://hdl.handle.net/1773/26103
dc.descriptionThesis (Ph.D.)--University of Washington, 2014en_US
dc.description.abstractThe primary objective of immune sensors is to differentiate self from non-self. Detection of viral genomes leads to activation of the antiviral response, accompanied by the production of type I interferons. However, these viral nucleic acids are very similar to host produced RNA and DNA. We investigate how human variants in SKIV2L, an RNA metabolism enzyme, can lead to erroneous interferon production by allowing an accumulation of self-RNA. While studying sources of the endogenous ligands that can accumulate, we considered the role of RNase L in the antiviral response. While the OAS/2-5A system and RNase L have been studied for many years, our findings suggest a new model for their function. We reveal that RNase L acts as a negative regulator of the antiviral response by eliciting global translational inhibition through cleavage of ribosomal RNA. We go on to show that the different 2-5A species synthesized by OAS proteins are endogenous immunostimulatory ligands, and that the OAS/2-5A system generates ligands for crosstalk between the RNA and DNA sensing and signaling networks within every cell. These studies have far-reaching implications for the detection of endogenous RNA ligands, their metabolism, and their association with autoimmune disorders. Furthermore, the reappraisal of RNase L and the new role for 2-5A species as endogenous activators of the antiviral response come with their own clinical implications, and allow for a more complete understanding of the early cellular response to viral pathogens.en_US
dc.format.mimetypeapplication/pdfen_US
dc.language.isoen_USen_US
dc.rightsCopyright is held by the individual authors.en_US
dc.subject2-5A; Antiviral Response; OAS; RNase L; SKIV2L; UPRen_US
dc.subject.otherImmunologyen_US
dc.subject.otherMolecular biologyen_US
dc.subject.otherimmunologyen_US
dc.titleRegulation and Endogenous Activators of the Cell-Intrinsic Antiviral Responseen_US
dc.typeThesisen_US
dc.embargo.termsRestrict to UW for 2 years -- then make Open Accessen_US
dc.embargo.lift2016-10-02T16:56:07Z


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