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Dr Trevor Sweeney

Dr Trevor Sweeney

Wellcome Sir Henry Dale Fellow

Division of Virology

Project:The molecular mechanism of protein synthesis

Division of Virology
Department of Pathology
University of Cambridge
Addenbrooke's Hospital
Hills Road,
Cambridge
UK

Office Phone: +44 (0)1223336072

Research themes

Virology:

Division

Virology:

Research Interests

Our lab studies the molecular mechanism of protein synthesis, with a specific focus on how different viruses interfere with this critical cellular process.

Virus translation  

Certain positive sense RNA viruses , such as poliovirus and foot-and-mouth disease virus, possess large highly structured 5’-untranslated regions in their genomes. These structures, referred to as IRESs (internal ribosomal entry sites), are capable of recruiting 40S ribosomal subunits to internal locations in the viral RNA genome, bypassing the requirement for canonical cap-dependent translation. We examine IRES function to determine which host factors are required to support their activity as well as their mechanism of stimulation. These studies are providing insights into our understanding of basic viral translation and cellular tropism important during infection. We are now expanding this research to study the non-canonical translation of other viruses that have alternatives to IRESs that facilitate efficient bypass of cap-dependent protein synthesis.

Flavivirus replication 

We have recently established a reverse genetics system for Zika virus to study the role of RNA structure in regulating the replication cycle of flaviviruses. We recently demonstrated that RNA-RNA interactions in the viral genome regulate its 'translatability' thus providing a mechanism to clear ribosomes for efficient replication. We are now investigating the role of viral and cellular factors in regulating this process. 

Immune regulation of virus translation

Another aspect of research in our lab is understanding the cellular response to infection and how the immune system specifically inhibits translation of viral RNAs. We characterized the mechanism of repression of viral translation by the interferon-induced proteins IFIT1 and IFIT5. Binding of these proteins to specific 5’-RNA ends that are recognized as ‘non-self’ directly inhibited their translation. We are now examining the downstream effects off IFIT/RNA recognition and the role of oligomeric complex assemblies in regulating the cells response to infection.

Research Supervision

Primary supervisor for four PhD students

Mr Thomas Sanford, Wellcome Trust funded Infection, Immunity and Inflammation PhD Programme (Year 4).

Miss Harriett Mears, Department of Pathology, Cambridge funded Studentship (Year 4).

Miss Skye Storrie, Wellcome Trust funded Infection, Immunity and Inflammation PhD Programme (Year 2).

Miss Xin Yun Leong, Malaysian Government funded PhD studentship (Year 2).

Key Publications

  1. Sanford TJMears HVFajardo T, JrLocker NSweeney TR. (2019) Circularization of flavivirus genomic RNA inhibits de novotranslation initiation. Nucleic Acids Res. DOI:10.1093/nar/gkz686
  2. Mears HV, Emmott E, Chaudhry Y, Hosmillo M, Goodfellow IG, Sweeney TR. (2019) Ifit1 regulates norovirus infection and enhances the interferon response in murine macrophage-like cells. Wellcome Open Res. DOI:10.12688/wellcomeopenres.15223.1.

  3. Fleith RC, Mears HV, Leong XY, Sanford TJ, Emmott E, Graham SC, Mansur DS, Sweeney TR. (2018) IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA. Nucleic Acids Res. 46(10):5269-5285

  4. Chavali PL, Stojic L, Meredith LW, Joseph N, Nahorski MS, Sanford TJ, Sweeney TR, Krishna BA, Hosmillo M, Firth AE, Bayliss R, Marcelis CL, Lindsay S, Goodfellow I, Woods CG, Gergely F. (2017) Neurodevelopmental protein Musashi 1 interacts with the Zika genome and promotes viral replication. Science, 357(6346):83-88

  5. Sweeney TR*, Kumar P*, Skabkin M, Skabkina O, Hellen CU, Pestova TV. (2014) Inhibition of translation by IFIT family members is determined by their ability to interact selectively with the 5’-terminal regions of cap0-, cap1- and 5’ppp- mRNAs. Nucleic Acids Res. 42(5)3228-45 (* Joint first author)
  6. Sweeney TR, Abaeva I, Pestova TV, Hellen, CU. (2014) The mechanism of translation initiation of Type 1 picornavirus IRESs. EMBO J., 33(1):76-92