Understanding antiviral stress granule (AVG) formation to develop a broad spectrum antiviral therapy (POWELL_U17DTP)
Lead Research Organisation:
University of East Anglia
Department Name: Graduate Office
Abstract
The recent outbreaks of harmful viruses such as Zika virus and Chikungunya virus around the world have shown the need for rapid and effective antiviral therapies. Even when vaccines are available, they take time to work, they are virus specific and they are expensive and time-consuming to administer. In this project, we will investigate how viruses are sensed by activation of the stress response in cells and try to identify small molecule inhibitors of stress which may act as a potent anti-viral drugs common to all types of virus. The stress response forms cytoplasmic protein aggregates called stress granules to halt protein translation and hence virus replication. Viruses have evolved strategies to overcome these granules, but recently a new type of antiviral granule (AVG) has been identified that we hope to exploit. In this project you will characterize AVGs using confocal live cell imaging, proteomic and translatome analysis. You will use high throughput DNA sequencing and bioinformatic techniques to identify global cell gene expression to find out important aways to amplify the antiviral response in cells.
Organisations
People |
ORCID iD |
| Penny Powell (Primary Supervisor) | |
| Benjamin Bone (Student) |
Publications
Jefferson M
(2019)
The Autophagy Protein ATG16L1 Is Required for Sindbis Virus-Induced eIF2a Phosphorylation and Stress Granule Formation
in Viruses
| Description | Sindbis virus (SINV) is a significant pathogen whose infection is known to induce the activation of elF2a, which in turn leads to the formation of stress granules. Stress granules are cytoplasmic pools of stalled transcripts, their formation being an antiviral response to infection. SINV also activates autophagy, a fundamental cellular process whereby the cell partitions and catabolises portions of itself in response to stress and infection. In our paper we showed a key player in autophagy, the protein ATG16L1 regulates elF2a activation as well as the translation of viral proteins and stress granule formation. The presence of ATG16L1 increases elF2a activation but also increases viral protein synthesis, which suggests that the virus can circumvent the antiviral nature of stress granules and still replicate. Removal of the ATG16L1 protein reversed these effects and also caused a overexpression of IFNBa and ISGs, which are antiviral cytokines. Overall ATG16L1 appears to be pro-viral for the SINV, aiding its replication even though it induces stress granule formation. |
| Exploitation Route | Stress granules are antiviral and inducing them could in some cases lead to attenuation of viral replication. This, therefore, offers a new avenue for the development of novel therapeutic interventions to viral disease, with these possible therapeutics being broad spectrum. |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| URL | https://www.mdpi.com/1999-4915/12/1/39/htm |