ORCID
https://orcid.org/0000-0003-3994-9291
Date of Award
9-12-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The interactions that occur between a virus and the infected cell determine the success of an infection. During negative-sense single-stranded RNA virus infections, copyback viral genomes (cbVGs) drive key virus-host interactions by activating the Mitochondrial Antiviral Signaling (MAVS) pathway that induces antiviral immunity and leads to reduced levels of virus replication. Whether cbVGs induce other cellular pathways and how these relate to their immunostimulatory activity is unknown. Here we show that cbVGs also induce a cellular stress response during pneumovirus and paramyxovirus infections. cbVGs activate the cellular stress response through Protein Kinase R (PKR) signaling, triggering translation inhibition and stress granule formation. The stress response is induced independent of MAVS signaling and does not have global effects on the antiviral immunity, demonstrating that cbVGs induce both pathways independently. The translation inhibition that accompanies the stress response leads to a reduction of virus protein levels that extends for several days after the initial infection. The work presented in this dissertation reveals a new cbVG-driven mechanism of viral interference where cbVGs induce a PKR-dependent cellular stress response that leads to reduction in viral protein expression without altering overall antiviral immunity. Elucidating the pathways that viruses activate in the cell and the effects these have in shaping the infection outcome broadens our understanding on the intricate evolutionary relationship between the pathogen and the host it infects. This knowledge will also serve as the basis for developing therapies that allow us to harness these virus-host interactions to combat RNA virus disease burden.
Language
English (en)
Chair and Committee
Carolina Lopez
Recommended Citation
Gonzalez Aparicio, Lavinia Jose, "Role of Copyback Viral Genomes in Activating Cellular Stress Responses During Pneumovirus and Paramyxovirus Infection" (2023). Arts & Sciences Electronic Theses and Dissertations. 3175.
https://openscholarship.wustl.edu/art_sci_etds/3175