Dissecting the role of RNA structure in respiratory virus replication

A Crick PhD position for the 2021 programme in the lab of David LV Bauer.

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 sense RNA viruses (paper in preparation) and negative sense RNA viruses (influenza A virus [1]).

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.

Dissecting the Role of RNA Structure in Respiratory Virus Replication

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.       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

3.       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