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- Genre: Masters Thesis
Description
Z-DNA binding protein 1 (ZBP1) is an interferon-inducible protein that plays a crucial role in antiviral defense by recognizing Z-form nucleic acid (Z-NA), a left-handed conformer of double-stranded DNA/RNA. When ZBP1 binds to Z-NA, it can trigger programmed cell death pathways, including apoptosis and necroptosis, in collaboration with receptor interacting protein kinases 1 and 3 (RIPK1 and RIPK3). Z-NA positive viruses including poxviruses and influenza A virus (IAV) activate ZBP1-dependent cell death during replication. Little is known whether ZBP1 plays any role during Z-NA negative virus infection. Doxycycline-inducible A549 ACE2 Tet-On cells were constructed to express ZBP1 and were infected with Z-NA negative viruses. ZBP1-expressing cells infected with Sindbis virus (SINV), La Crosse virus (LACV), Vesicular stomatitis virus (VSV) and human coronavirus OC43 (hCoV-OC43) underwent extensive cell death, which could be rescued by a caspase inhibitor but not by JAK1/2 or RIPK1 kinase inhibitors. However, cell death was not observed upon Zika virus (ZIKV), Encephalomyocarditis virus (EMCV), Chikungunya virus (CHKV) or human coronavirus 229E (hCoV-229E) infection. ZBP1 expression did not impact the replication of all tested viruses. In addition, ZBP1-mediated cell death during infection depends on the Zα2 and RHIM1 domains and partially on the C-terminal domain. These findings suggest that Z-NA can be detected by the Zα2 domain to initiate cell death pathways during infection with some Z-NA negative viruses and that the RHIM1/C-terminal domains are necessary for ZBP1-induced cell death. Further research is needed to determine the Z-NA ligand and the precise mechanism of ZBP1-mediated antiviral responses and how they can be exploited for the development of novel antiviral therapies.
ContributorsLa Rosa, Bruno Andres (Author) / Li, Yize (Thesis advisor) / Jacobs, Bertram (Committee member) / Hogue, Brenda (Committee member) / Arizona State University (Publisher)
Created2023
Description
Myxoma virus (MYXV), a Leporipoxvirus, is being developed as an oncolytic agent against various types of human cancers. It successfully infects and has oncolytic effects on cancer cells while remaining nonpathogenic to normal human cells and all other non-leporid species. To develop virus constructs and maximize their effectiveness against cancer cells, the interaction between virus and host should be well characterized. DEAD-box RNA helicase DDX3 was previously identified as an intrinsic host factor that regulates MYXV replication in human cancer cell lines. Here, it is reported that transient knockdown of DDX3 in human cancer cells significantly enhances MYXV replication and progeny virus production. In uninfected cells, DDX3 localizes throughout the cytoplasm of human cells; however, in the MYXV-infected cells, DDX3 localizes to the perinuclear region of the cells and forms granule-like particles. It is further demonstrated that DDX3 is likely enhancing the type-1 interferon (IFN) production as the expression of the cytokine is decreased when DDX3 is knocked down during MYXV virus infection. Thus, the absence of DDX3 significantly enhanced myxoma virus spread by reducing the production of type-1 IFN and IFN-mediated signaling. These results suggest that DDX3 is a potential cellular target for enhancing the oncolytic activity of MYXV in human cancers.
ContributorsMunig, Saige (Author) / Rahman, Masmudur (Thesis advisor) / McFadden, Grant (Thesis advisor) / Li, Yize (Committee member) / Arizona State University (Publisher)
Created2024