Work in my laboratory focuses on EROS (Essential for Reactive Oxygen Species) protein. This novel endoplasmic reticulum transmembrane protein controls the abundance of a select group of proteins that play key roles in innate and adaptive immunity. I characterised the protein, working with Ken Smith and Gordon Dougan in Cambridge and have now set up my own group at Imperial College. EROS was identified through the Sanger Institute’s Knockout Mouse Programme because EROS-deficient mice (previously gene symbol bc017643, now cybc1) died very quickly following infection with Salmonella Typhimurium. Clearance of Salmonella is dependent on production of reactive oxygen species via the phagocyte respiratory burst. We showed that EROS protein is essential for the production of reactive oxygen species in both mouse and human because it is essential for expression of the gp91phox-p22phoxcomponents of the phagocyte NADPH oxidase complex. Subsequently we demonstrated that EROS deficiency in humans can cause Chronic Granulomatous Disease (CGD), a monogenic immunodeficiency. We have now explored the mechanism by which EROS controls gp91phox-p22phox abundance and are preparing these results for publication.
Moreover, we find that EROS also regulates the expression of many other key proteins. For example, EROS-deficient macrophages express very low levels of P2X7, an ion channel that binds extracellular ATP and drives activation of the NLRP3 inflammasome. P2X7 is also very lowly expressed in EROS deficient human cells. Eros co-immunoprecipitates with P2X7 and both P2X7 driven calcium flux and inflammasome activation are markedly abnormal in Eros-deficient cells with highly impaired production of IL-1b, reduced caspase 1 cleavage and reduced ATP-induced cell death.
Together, the loss of both the phagocyte respiratory burst and P2X7 signalling lead to marked resistance to some viral infections in marked contrast to bacterial infection.
The laboratory now focuses predominantly on the biochemistry and cell biology of how EROS regulates the abundance of certain proteins and its role in other cell types, both in the immune system and non-immune cells.
SELECTED PRIZES AND AWARDS
2017 Wellcome-Beit Prize
2016 Stewart Cameron Science Award (Royal Society of Medicine)
2016 FOCIS Prize for top-scoring Abstract at FOCIS meeting, Boston, MA, USA
2016 Runner-Up in Lancet Young Investigator Prize - Academy of Medical Sciences
2014 Oral plenary prize for best presentation – Academy of Medical Sciences Winter Meeting
2005 Roger Morris Prize, University of Cambridge
2005 John Fawcett Prize, University of Cambridge