Exploring mechanisms of virus interaction with host cells
Intracellular Immunity Team
The goal of our work is to identify novel genes and map intracellular pathways involved in virus:host interactions.
Infected cells need to sense and respond appropriately to viral infection.
In turn, viruses manipulate host cell signalling pathways to enable viral replication and evade immune recognition
To identify cellular processes targeted by viruses, my lab uses functional proteomics to characterise changes in intracellular and cell surface proteins during viral infection. We have previously discovered hundreds of proteins to be dysregulated in HIV-infected “helper” T cells, including cell surface amino acid transporters.
More recently, I have been closely involved with the Cambridge University Hospitals response to the COVID-19 pandemic, and my lab has reoriented towards the fight against SARS-CoV-2. We are therefore now developing cell-based assays for proteomic, genetic and small molecule screens in coronavirus infection, with the ultimate aim to deliver novel therapeutics to the clinic.
My research is focused on understanding the early driver events that are critical to the development of squamous lung cancer (SQC) and translating this knowledge into novel approaches to early detection and novel therapeutics or chemoprevention agents.
We have evidence that amplification and deregulation of SOX2 is a key event in the pathogenesis of SQC. We have developed novel preclinical model systems to deconstruct the functional impact of SOX2 activation in the pathogenesis of this disease and to define therapeutic vulnerabilities.
Infected or diseased tissues result in hostile oxygen and nutrient poor environments, and this is particularly evident in the acute lung injury observed with SARS-CoV-2. Our goal is to dissect the pathways that allow cells survive these conditions, providing potential new therapeutic targets. We are using a combination of biochemical and cell biological approaches to understand how cells respond to oxygen and nutrient availability, and how this can modulate SARS-CoV-2 infection.
I have been leading Cambridge-based COVID-19 testing for Addenbrooke’s staff, and Cambridge University staff and students (https://elifesciences.org/articles/58728, https://elifesciences.org/articles/58728).
Additionally, my lab has been conducting innovative research aimed at determining how to predict which patients with COVID-19 will need intensive care. By using a technique called proteomics, we can determine which proteins are present at the surface of white blood cells from patients in ITU compared to those with milder or even asymptomatic disease. Identification of these proteins will not only aid clinical decision-making but will also aid our understanding of disease processes.
My lab’s overall aim is to develop new treatments for vascular diseases, in particular those involving vascular smooth muscle cells (SMC), using a stem cell based approach. We have pioneered the generation of embryonic lineage-specific vascular SMC, through the lateral mesoderm, paraxial mesoderm, neural crest and epicardium, from human embryonic stem cells (hESC) and induced pluripotent stem cells, using chemically defined conditions. We have utilised this system to model genetically triggered aortopathies, such as Marfan and Loeys-Dietz syndromes. These “disease-in-a-dish” models are being used to understand the pathobiology of these conditions and to screen for new treatments.
One third of all currently used medicines target G-protein-coupled receptors (GPCRs) belonging to Class 1 or Family A, part of the ‘druggable genome’.
The aim of the study is to test medicines currently in use but for other conditions, as well as new compounds, to determine if they block entry of the SARS-CoV-2 virus into human cells growing in the laboratory. The study will concentrate on a special protein on the cell surface called ACE2 that the virus must bind, in order to enter the patient’s tissues, such as the lungs and heart. The most promising compounds shown to block viral entry would undergo further laboratory testing with the objective of identifying new candidates to test in clinical trials of patients infected with the virus.
The main objThe main objective of our group is to define the molecular mechanisms controlling the transition between pluripotency and the endoderm lineage. For that, we use human pluripotent stem cells (hESCs and hIPSCs) and organoids as in vitro models of development to study the interplays between transcriptional networks, epigenetic modifications and cell cycle which ultimately orchestrate the earliest step of differentiation. The resulting knowledge allows the development of new culture systems to produce liver, pancreatic, lung and gut cells. These cells are then used for modelling diseases in vitro and for cell-based therapy.