
Biography
I studied Genetics as an undergraduate at University of Nottingham, where I first became fascinated with RNA and post-transcriptional control of gene expression. Moving to Edinburgh for my PhD at the MRC Human Genetics Unit, I worked under the supervision of Nicola Gray investigating the regulation and function of poly(A)-binding proteins in stress conditions, including infection. I subsequently moved to the USA to join Ian Mohr’s lab at NYU School of Medicine. There I conducted multiple post-doctoral projects using different viruses (Vaccinia, HSV-1, HCMV, coronaviruses including SARS-CoV-2) to investigate how host and viral control of mRNA decay, modification and translation influences infection. I joined University of Surrey’s Department of Microbial Sciences as a lecturer and research group leader in 2022.
Affiliations and memberships
Research
Research interests
My research interests lie at the intersection of mRNA metabolism and virus infection, investigating how viral and host factors that influence mRNA processes impact infection in sometimes unexpected ways. Key research areas we’re currently exploring are:
- Understanding how RNA m6A methylation controls coronavirus infections, including SARS-CoV-2
- The role of host RNA decay pathways in Human Cytomegalovirus (HCMV) infection
- The importance of circular RNAs in viral infections
My teaching
BMS2036 - MOLECULAR BIOLOGY AND GENETICS: FROM GENES TO BIOLOGICAL FUNCTION
BMS2037 - CELLULAR MICROBIOLOGY AND VIROLOGY
My publications
Publications
Regulated loading of eIF3-bound 40S ribosomes on capped mRNA is generally dependent upon the translation initiation factor eIF4E; however, mRNA translation often proceeds during physiological stress, such as virus infection, when eIF4E availability and activity are limiting. It remains poorly understood how translation of virus and host mRNAs are regulated during infection stress. While initially sensitive to mTOR inhibition, which limits eIF4E-dependent translation, we show that protein synthesis in human cytomegalovirus (HCMV)-infected cells unexpectedly becomes progressively reliant upon eIF3d. Targeting eIF3d selectively inhibits HCMV replication, reduces polyribosome abundance, and interferes with expression of essential virus genes and a host gene expression signature indicative of chronic ER stress that fosters HCMV reproduction. This reveals a strategy whereby cellular eIF3d-dependent protein production is hijacked to exploit virus-induced ER stress. Moreover, it establishes how switching between eIF4E and eIF3d-responsive cap-dependent translation can differentially tune virus and host gene expression in infected cells.
With their categorical requirement for host ribosomes to translate mRNA, viruses provide a wealth of genetically tractable models to investigate how gene expression is remodeled post-transcriptionally by infection-triggered biological stress. By co-opting and subverting cellular pathways that control mRNA decay, modification, and translation, the global landscape of post-transcriptional processes is swiftly reshaped by virus-encoded factors. Concurrent host cell-intrinsic countermeasures likewise conscript post-transcriptional strategies to mobilize critical innate immune defenses. Here we review strategies and mechanisms that control mRNA decay, modification, and translation in animal virus-infected cells. Besides settling infection outcomes, post-transcriptional gene regulation in virus-infected cells epitomizes fundamental physiological stress responses in health and disease.
The mRNA 5' cap structure serves both to protect transcripts from degradation and promote their translation. Cap removal is thus an integral component of mRNA turnover that is carried out by cellular decapping enzymes, whose activity is tightly regulated and coupled to other stages of the mRNA decay pathway. The poxvirus vaccinia virus (VACV) encodes its own decapping enzymes, D9 and D10, that act on cellular and viral mRNA, but may be regulated differently than their cellular counterparts. Here, we evaluated the targeting potential of these viral enzymes using RNA sequencing from cells infected with wild-type and decapping mutant versions of VACV as well as in uninfected cells expressing D10. We found that D9 and D10 target an overlapping subset of viral transcripts but that D10 plays a dominant role in depleting the vast majority of human transcripts, although not in an indiscriminate manner. Unexpectedly, the splicing architecture of a gene influences how robustly its corresponding transcript is targeted by D10, as transcripts derived from intronless genes are less susceptible to enzymatic decapping by D10. As all VACV genes are intronless, preferential decapping of transcripts from intron-containing genes provides an unanticipated mechanism for the virus to disproportionately deplete host transcripts and remodel the infected cell transcriptome.