BindCGRNA

Collectively, infectious diseases are the leading cause of death in the world, and in the UK alone, infectious diseases account for annual costs of £ 30 billion. To control disease spread, immunisation programmes have been the most effective public health intervention; but progress in this area has been deterred by the emergence of new virus variants, zoonotic transmission and vaccine manufacturing costs.

Contributing to the failure in controlling infectious diseases, viruses can also rapidly evolve to circumvent our immune defences, allowing them to persist and cause disease. Despite considerable progress in our understanding of the immune response to viral infections, mechanisms underlying viral immune evasion remain inadequately understood.

Live-attenuated virus vaccines offer a great way to provide immunity since they mimic the morphology and antigen repertoire of natural infections, eliciting protective immune responses while having little or no side effects during immunisation. However, strategies for the rational design of live-attenuated vaccines are scarce and poorly understood. Recent advancements in DNA synthesis have fuelled a new wave of vaccines generated by the introduction of numerous synonymous mutations in viral genomes.

This type of vaccine can be quickly generated and is robust and stable. One such strategy involves the introduction of CpG dinucleotides, i.e. a cytosine followed by a guanine, in viral genomes rendering viruses extremely sensitive to immune defences. However, I have recently discovered that certain arrangements of CpGs are resistance to attenuation and, surprisingly, can circumvent innate immune defences by inducing their degradation.

It is likely that certain human viruses with high CpG content may use this strategy to evade immune responses. This has exposed an Achilles' heel in the efficaciousness of CpG-derived live-attenuated vaccines that needs to be urgently addressed.

The overall aim of this project is to discover how certain CpG arrangements in virus RNA are sensed by human cells and how that triggers the degradation of immune defences. Specific aims include: - To understand how currently circulating viruses may use CpG patterns to evade immune responses - To identify genes involved in the detection of CpG dinucleotides in virus RNA

- To understand which arrangements of CpGs cause the degradation of innate immune defences - To devise a novel vaccine design strategy that preserves attenuation without degrading immune defences

The main application of this research lies on the development of a novel vaccine design strategy that is safe to use and can be applied to all viruses. This project will also identify novel gene targets for therapeutic intervention. The benefits of such technology will greatly impact the economy, as new vaccines using this design can then be manufactured, protecting society from emerging diseases.

The need for rapid vaccine development in face of novel infectious disease is likely to increase in the near future, as the permanent change to the climate in the UK is likely to attract animal species that are vectors for numerous viral diseases. The implementation of adequate technologies and infrastructures will protect the UK population from future zoonotic virus transmissions.