Potential Supervisors within this theme
Prof Simon Arthur
Inflammation is critical to the host response to infection or damage. Excessive inflammation is however harmful and as a result this process is closely controlled by both pro- and anti-inflammatory factors. Failure of these processes can result either failure to control a pathogen or chronic inflammation. We are interested in the roles that cells in the innate immune system play in coordinating inflammation and how they contribute to activation of adaptive immunity via the production of cytokines and other inflammatory mediators. Innate immune cells recognize specific components of pathogens – referred to as pathogen associated molecular patterns or PAMPs. Several groups of receptors for PAMPs have been described, including Toll like receptors, C-type lectins and NOD-like proteins. These receptors trigger the activation of several intracellular signaling pathways, including the mitogen activated protein kinase (MAPK), NFkappaB and TBK1/IRF systems leading to the transcription and production of both pro- and anti-inflammatory cytokines. Our main focus is to understand the roles these intracellular signaling cascades play in both the initial inflammatory response and in the ability of innate immune cells regulate the inflammatory process. In this context we are focused on their roles in responses to fungal pathogens and long term immune conditions such as asthma and arthritis.
Prof Doreen Cantrell
The research program adopts a multidisciplinary approach and combines biochemistry, cell biology and in vivo mouse immunology to map how antigen receptor, cytokine and environmental signals integrate to control the function of T lymphocytes. One important component of the work is a discovery based program to use high resolution mass spectrometry to systematically define how changes in environment modulate the proteomes of naïve and effector CD4 and CD8 T lymphocyte subpopulations. Specifically, we will comprehensively delineate the molecular details of how changing the supply of nutrients impacts T cell signal transduction pathways and T cell phenotype. These experiments will identify the molecular processes that determine T cell fate outcomes.
Prof Philip Cohen
My research focuses on how the innate immune system is regulated by the interplay between protein phosphorylation and protein ubiquitylation events. Major ongoing projects include understanding how the E3 ubiquitin ligase TRAF6 prevents the uncontrolled activation of T cells to prevent autoimmunity, and how the ubiquitin-binding protein ABIN1 restricts Toll-Like Receptor signalling pathways to prevent lupus. Following our recent discovery that the E3 ligase HOIL-1 forms unique ester bonds between ubiquitin and its target proteins, we are studying the role of HOIL-1 in controlling innate immunity and other biological processes. Another major project is to understand how the SIK subfamily of protein kinases control cytokine production in mast cells and we are evaluating their potential as drug targets for the treatment of asthma and other diseases, in collaboration with Simon Arthur.
Dr Sarah Coulthurst
Our overall research interests are bacterial protein secretion systems (sophisticated machineries that translocate bacterial proteins into other cells or the environment) and mechanisms of inter-bacterial competition. These converge in our primary research area – the mechanisms, role and regulation of the bacterial Type VI secretion system. The Type VI secretion system is a nanomachine that many different bacterial species use to deliver toxic effector proteins into rival bacteria, and can also be used against eukaryotic cells including microbial fungi. We are a molecular microbiology group who use a combination of bacterial genetics, molecular biology, cell biology, biochemistry and ‘omics approaches
Dr Helge Dorfmueller
My lab studies the Group A Carbohydrate (GAC) biosynthesis pathway, a surface virulence factor in Group A Streptococcus. Our aims are to obtain molecular and structural insights into the enzymes that synthesise the carbohydrate and to exploit these new drug targets with inhibitor screening. Furthermore, my lab explores the GAC as a vaccine candidate, combining glyco-engineering with host immunity responses and GAS infection models.
Prof David Horn
The African trypanosome, Trypanosoma brucei, is transmitted among mammalian hosts by tsetse flies. These unicellular parasites cause Human African Trypanosomiasis, also known as sleeping sickness, which is typically fatal if left untreated, and the livestock disease known as nagana. Molecular mechanisms underlying antigenic variation, drug action and other fundamental processes remain to be characterised. We typically use genetic screens for unbiased genome-scale functional analysis. We then focus on the genes and proteins that play major roles in virulence, with a view to the development of improved therapies.
Dr Henry McSorley
The chronic intestinal helminth parasite of mice, Heligmosomoides polygyrus, has many immunomodulatory effects, including the ability to suppress pathology in mouse models of asthma, colitis and autoimmune disease. The collected excretory/secretory products of H. polygyrus (HES) can replicate many of the immunomodulatory effects of infection, including suppression of pathology in models of immune-mediated diseases. In mouse models of asthma, we have shown that HES can suppress immune responses initiated using an alum adjuvant or extracts of the fungal allergen, Alternaria alternata. In both models, suppression is dependent on HES acting on the very earliest events in allergic response initiation. In the Alternaria model in particular, HES suppressed IL-33 release within the first hour after allergen administration, resulting in reduced ILC2 activation and ultimately a smaller type 2 response and reduced pathology in the lungs. We aim to identify the individual molecules in HES responsible for its immunomodulatory effects, with a view to producing these (or derivatives of these) as potential therapeutic agents for human disease. In conjunction with this work, we aim to dissect the mechanisms by which HES suppresses the release of IL-33, as this may give us new insights into the biology of IL-33, ILC2 responses and asthma in general.
Prof Nicola Stanley-Wall
My laboratory is interested in how bacteria form complex sessile communities called biofilms. Once formed, biofilms impact many aspects of our life and are, for example, the cause of chronic antimicrobial tolerant infections. To understand the processes underpinning biofilm formation, we use a range of approaches including genetics, biochemistry and biophysics and coupled them with imaging methods.
Dr Mahima Swamy
Our research aims to study the function and regulation of intraepithelial lymphocytes. These are a class of poorly characterised innate-like T cells that reside in the intestinal epithelium, and are central to controlling infection, stress or transformation of the gut epithelium. Understanding the roles of intraepithelial lymphocytes will lead to better understanding of diseases such as inflammatory bowel disorders, infections and cancer.