Project: Replication and pathogenicity of intestinal RNA viruses
Characterisation of the novel uORF in enteroviruses
We have recently reported that enteroviruses encode an additional protein in an upstream open reading frame (uORF). Knocking out expression of the uORF protein (termed “UP”, Upstream Protein) attenuates virus growth at late stages of infection in human intestinal organoids but not in standard cell culture systems, suggesting a specific role for UP during establishment of infection in gut epithelia in the initial stages of virus invasion into susceptible hosts (Lulla et al., Nature Microbiology, 2019). Current work focuses on understanding how UP expression is controlled, the role(s) of UP in different enterovirus species, characterisation of UP-mediated virus release in gut epithelial cells as well as potential related vaccine strategies.
Characterisation of astrovirus replication and pathogenicity
Astroviruses are one of the most prevalent groups of human RNA viruses. However, they are critically understudied because of the lack of good molecular tools and animal models. Despite the appearance of recently emerged strains and increasing detection of astroviruses as previously overlooked causative agents of gastroenteritis, the current lack of molecular understanding and expertise precludes the efficient development of therapeutic approaches. We have recently identified and characterised a new ORF encoded by astroviruses (Lulla and Firth, Nature Communications, 2020) and already used the developed astrovirus replicon system to aid a SARS-CoV-2 related project (Lulla et al., Journal of Virology, 2021). This project will focus on understanding the formation of the astrovirus replication complex, RNA synthesis mechanisms, proteolytic processing, gut-specific determinants, and the molecular mechanisms responsible for neurovirulence.
Funding for our research comes from the MRC, the Royal Society and the Wellcome Trust.
Group members:
Rhian O’Connor (PhD student)
David Noyvert (PhD student)
Dr Jacqueline Hankinson (Postdoctoral research associate)
Ksenia Fominykh (Research assistant)
Adam Rayment (PhD student, joint with Pirbright Institute)
Past lab members:
Dr Hashim Ali (2021-2023, PDRA, now at UCL), Gemma Lindsey (part II student), Samantha Cheng (EPLS Summer student), Morgan Reid (EPLS Summer student), and Imran Darr (part II student).
