Dissecting the role of RNA structure in respiratory virus replication

A Crick funded PhD position for the 2022 programme in the lab of David Bauer.

Applications are now closed

We are no longer accepting applications for the 2022 PhD student programme. If you submitted an application by the deadline, check our applicant information pages.

See applicant information
RNA virus assay.

Project background and description

 

The majority of human respiratory viruses encode their genome as RNA, including those that cause COVID-19 and Influenza. Unlike DNA, RNA can encode information and function in its structure as well as its sequence. This feature is exploited by all RNA viruses in one way or another. Coronaviruses, for example, use RNA structures to regulate their own genome replication, as well as to interact with host ribosomes. Influenza viruses use RNA structure to control splicing of viral genes and to drive reassortment of its eight genomic segments — the process that gives rise to new pandemic strains. Much of the details about how RNA structures act (and interact) during infection, however, remains unknown.

This project aims to discover and characterise RNA structures within infected cells by building on our recent breakthroughs in understanding genome structure of viral RNA of positive and negative sense RNA viruses [1] — as well as budding understanding of features that may affect virus replication and pathogenicity, especially in the context of vaccine escape [2].

Specifically, we will examine how RNA structures change throughout the course of infection using established chemical probing methods coupled with high-throughput sequencing (e.g. SHAPE-MaP). In order to explore the function of these structures, we will also examine which cellular and viral components they interact with (e.g. using crosslinking and mass spectrometry). Lastly, we will characterise the functions of these structures by disrupting them through mutagenesis or with antisense oligonucleotides, and examining the resulting effects on viral growth and pathogenesis both in vitro and in vivo.

Overall, this project will contribute significantly to our understanding of RNA virus biology. There is also potential for immediate impact on the treatment of respiratory viruses: RNA structures are often highly conserved, making them attractive targets for new classes of antiviral drugs that are critical in the absence of effective vaccines. Our group and our collaborators have extensive ongoing efforts in this area, and we will be able to rapidly evaluate discoveries made as part of this project for translation to the clinic.

Candidate background

 

This project would suit candidate with a strong background in molecular biology, biochemistry, or related fields with an interest in virology. Our group and the Crick environment are strongly interdisciplinary, and applications are welcome from those without specific prior virology or bioinformatics expertise.

References

 

1.         Dadonaite, B., Gilbertson, B., Knight, M.L., Trifkovic, S., Rockman, S., Laederach, A., . . . Bauer, D.L.V. (2019)

            The structure of the influenza A virus genome.

            Nature Microbiology 4: 1781-1789. PubMed abstract

2.         Wall, E.C., Wu, M., Harvey, R., Kelly, G., Warchal, S., Sawyer, C., . . . Bauer, D.L.V. (2021)

            Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination.

            The Lancet 397: 2331-2333. PubMed abstract

3.         Ferhadian, D., Contrant, M., Printz-Schweigert, A., Smyth, R.P., Paillart, J.C. and Marquet, R. (2018)

            Structural and functional motifs in influenza virus RNAs.

            Frontiers in Microbiology 9: 559. PubMed abstract

4.         Sola, I., Almazán, F., Zúñiga, S. and Enjuanes, L. (2015)

            Continuous and discontinuous RNA synthesis in coronaviruses.

            Annual Review of Virology 2: 265-288. PubMed abstract