Alexander Khromykh

Cooperation between sfRNA and non-structural protein NS5 for flavivirus immune evasion

This Earmarked Scholarship project is aligned with a recently awarded Category 1 research grant. It offers you the opportunity to work with leading researchers and contribute to large projects of national significance.

Flaviviruses are important human pathogens that include West Nile, Dengue, Zika, Yellow fever virus and other viruses. They have a unique ability to produce viral noncoding RNA from their 3' untranslated region by hijacking host exoribonuclease. This RNA, termed subgenomic flaviviral RNA (sfRNA), accumulates in infected cells in high abundance and facilitates viral pathogenesis by supressing antiviral response. However, the molecular mechanism that determines this activity is not fully elucidated. Recently we have discovered that sfRNA of Zika virus executes this function in cooperation with the viral protein NS5. We found that sfRNA binds to and stabilises NS5, allowing this protein to inhibit phosphorylation of transcriptional factor STAT1, a key mediator of antiviral signalling.

This project is aimed to uncover how sfRNA binding effects NS5 conformation and its ability to inhibit STAT1 phosphorylation by identifying interacting sites in both molecules, characterising structural changes in NS5 caused by sfRNA binding and creating mutant viruses incapable of sfRNA-NS5 interactions. It will also investigate whether this mechanism is conserved between all flaviviruses.

The successful candidate will have an opportunity to join one of the leading flavivirus laboratories and work in the dynamic team of internationally recognised experts at the forefront of flavivirus research. He/she will obtain experience in the wide range of classical and modern research techniques such as cryo-electron microscopy, next generation sequencing, generation of mutant viruses, immunofluorescent virus detection, quantitative PCR, Northern blotting, electrophoretic mobility shift assay, etc. He/she will have an opportunity to communicate their research at the national and international conferences and publish in the leading academic journals.

Predicting and preparing for the unfolding evolution of SARS-CoV-2

This Earmarked Scholarship project is aligned with a recently awarded Category 1 research grant. It offers you the opportunity to work with leading researchers and contribute to large projects of national significance.

SARS-CoV-2 is the cause of current COVID-19 pandemic which has already infected >270 million people and killed >5 million of them. Currently deployed and future vaccines are likely to significantly decrease the burden of pandemic, however, new viral variants are emerging that are less susceptible to vaccine-induced immunity. Hence, deeper understanding of what drives viral evolution under the pressure of vaccine-induced immune responses is needed to predict and prepare for the emergence of future variants and inform development of more effective vaccines. The project will employ deep mutational scanning methodology to identify changes in the viral spike protein responsible for altered susceptibility to vaccine-induced antibodies. The implications of identified changes on the properties of spike protein and susceptibility to vaccine-induced antibodies will be investigated using structural analysis and various functional assays. The findings will be critical for predicting viral changes that are likely to emerge in the landscape of vaccinations and provide invaluable information for pre-emptive development of vaccines that will be able to minimise future emergence of vaccine-resistant variants.