Control of translation and stress granules by coronaviruses
| Autor: | BROWNSWORD, MATTHEW |
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| Rok vydání: | 2022 |
| Předmět: | |
| DOI: | 10.15126/thesis.900264 |
| Popis: | Infectious bronchitis virus (IBV) is a Gammacoronavirus and the causative agent of infectious bronchitis (IB). IB is a prevalent disease of chickens that severely affects the global poultry industry as disease results in reduced weight gain and egg production. SARS-CoV-2, a Betacoronavirus, is the causative agent of the ongoing Covid-19 pandemic, resulting in over 4.7 million deaths. Due to the endemic and pandemic nature of these viruses and the incalculable combined effect they have on the world, improved understanding of virus host interactions is essential to inform on effective antiviral targets, which could have wider applications to improve animal and human health. In this thesis, the viral antagonism of cellular translation and stress granule (SG) assembly is characterised during IBV infection and conserved protein functions between IBV and SARS-CoV-2 are investigated. SGs are membranelles organelles that form in the cytosol in response to cellular stress and function to restore homeostasis. In this work it is shown that IBV replication inhibits SGs induced via multiple mechanisms yet results in SG assembly in a sub-population of mammalian and avian cells despite the absence of canonical markers of SG signalling. Additionally, it is shown that IBV infection induces translation inhibition in both mammalian and avian cells, and this shut off was uncoupled from SG assembly in Vero cells. Finally, two viral proteins, the nucleocapsid (N) protein and the endoribonuclease, non-structural protein 15 (nsp15), from IBV and SARS-CoV-2 are shown to share functions and mechanisms of SG antagonism. The CoV nsp15 is shown to inhibit SG assembly induced by NaAs. Furthermore, the N protein of SARS-CoV-2 is shown to phase separate, a feature that governs the formation of SGs, colocalise with SG marker G3BP1 and inhibit SG assembly. Therefore, both IBV and SARS-CoV-2 share SG antagonistic functions. This work contributes to the furthered understanding of CoVs protein function conservation and highlights possible targets for production of pan-CoV antivirals. |
| Databáze: | OpenAIRE |
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