Abstract
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.