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http://hdl.handle.net/11375/26950
Title: | p14 viral fusion protein driven cell-cell fusion induces micronuclei formation and a STING-dependent interferon response |
Authors: | Murdza, Tetyana |
Advisor: | Mossman, Karen |
Department: | Biochemistry and Biomedical Sciences |
Keywords: | Stress induced interferon responses |
Publication Date: | 2021 |
Abstract: | The innate immune system is the first line of defence against viral infections. Conventionally, innate immune activation begins with the detection of foreign nucleic acids by pattern recognition receptors (PRRs), which triggers a signalling cascade that culminates in the production of interferon (IFN) and other inflammatory cytokines and chemokines. Over the past few years, a number of studies have shown that IFN innate immune responses can also be triggered by stressors, such as membrane perturbations, cytoskeletal perturbations, oxidative stress, and endoplasmic reticulum (ER) stress 1–3. One way that some viruses provoke such stress responses is through membrane and cytoskeletal distortions during enveloped virus particle entry. In some cases, the glycoproteins responsible for virus particle entry can also trigger cell-cell fusion. The potential of cell-cell fusion to induce stress-based IFN responses analogous to those triggered by virus-cell fusion has not been addressed until very recently. To investigate if and how cell-cell fusion may induce antiviral mechanisms and IFN responses we used the reptilian reovirus p14 fusion associated small transmembrane (FAST) protein as a model of cell-cell fusion. We found that p14-mediated cell fusion led to the production of low level IFN and upregulation of interferon stimulated genes (ISGs) in a stimulator of interferon genes (STING) and interferon regulatory factor 3 (IRF3) dependent manner. We also observed that multinucleated cells experienced extensive DNA-damage that led to the accumulation of cytosolic DNA in the form of micronuclei. Micronuclei can be detected by cytosolic DNA PRRs like cyclic GMP-AMP synthase (cGAS) and signal IFN production through the cGAS-STING signalling axis. Additionally, early syncytia formation restricted replication of vesicular stomatitis virus (VSV), herpes simplex virus-1 (HSV), and vaccinia virus (VSV) in an IFN and IRF3 independent, and STING dependent manner, suggesting involvement of either a novel antiviral mechanism or suppression of virus replication and spread by biological changes in syncytial cells, such as cell cycle arrest. This study highlights a key role of DNA sensing pathways in the immune response to cell fusion associated stress and points out the importance of fusion kinetics in the selective advantage of syncytial viruses. Understanding the potential of syncytial cells to induce IFN responses and influence viral replication at a mechanistic level is beneficial to the design of improved oncolytic immunotherapy. |
URI: | http://hdl.handle.net/11375/26950 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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murdza_tetyana_202109_masterofsciencebiochemistry.pdf | 60.2 MB | Adobe PDF | View/Open |
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