Our immune system protects us against infection, but may cause disease if not properly regulated. Understanding how the immune response is triggered and controlled is thus an important area of research. This group brings together basic scientists and clinicians to link our laboratory-based studies with clinical applications to drive improved diagnostic and therapeutic strategies for infectious disease and other conditions, including cancer and neurodegeneration. We focus on the following.
- Innate immunity, in particular how host immune cells sense and respond to pathogens.
- Antimicrobial resistance and the development of novel antimicrobial therapies.
- Viral pathogenesis and the application of self-disseminating viral vaccines.
- We are using cell models of infection to reduce and replace the use of animals in infection research as part of our commitment to the 3R agenda.
Retroelements and Disease
Around half of our genome sequence is made up of retroelements. These are genomic parasites that have been proliferating within our genome for millions of years. Building on my background in studying their evolution, we are now examining several possible roles of retroelements in human disease and therapy. For example, some appear to be contributing to Merlin-deficient tumour proliferation, where they could offer a promising druggable target. We are also examining the extent to which they interact with the innate immune system, with implications for autoimmune/inflammatory disease and vaccine design.
Matthew heads the Hepatology Research Group, who carry out a range of clinical and research projects here at Plymouth. This focuses on protection from hepatitis C virus infection (Matthew Cramp); lipid metabolism and the pathogenesis and treatment of non-alcoholic steatohepatitis (David Sheridan); alcoholic hepatitis (Ashwin Dhanda); and molecular virology of hepatitis viruses (Dan Felmlee).
Molecular mechanisms of lung macrophage functions
Macrophages are crucially involved in various infectious diseases, cancer, metabolic disorders and also in normal tissue homeostasis. Studies are hampered by the limited life-span and restricted numbers of primary tissue macrophages that can be obtained for experiments. We have therefore established a novel, continuously growing, non-transformed model of lung alveolar macrophages (AMs), cells that play key roles in important diseases such as lung infection, asthma and chronic obstructive pulmonary disease. This new system has already made possible the identification of several, previously unknown, innate immune phenomena in AMs and we are now analysing the underlying molecular details to allow development of drugs that can influence AM activity in various pathology states.
Image shows AMs in culture
Macrophages are at the forefront of immune defence against pathogens and tumours. They exhibit a degree of functional plasticity which, when dysregulated, contribute to inflammatory pathology and cancer. Research centres on the role of mucosal macrophages in homeostasis and pathology; with the specific aim of manipulation of plasticity and functional activation/suppression as a future cell-based therapeutic regimen in the treatment of gut diseases (Crohn’s disease, ulcerative colitis, colorectal cancer) and oral mucosal diseases (chronic periodontitis and oral squamous cell carcinoma).
The skeleton constantly remodels in response to changes in mechanical load, serum calcium and micro-damage. This dynamic process generates a bone mass and structure optimised to current physical and mineral requirements. At a cellular level remodelling is performed by osteoblasts that secrete and mineralise new bone matrix and osteoclasts that resorb bone. Osteoblast and osteoclast activity is tightly regulated such that during each remodelling cycle osteoblast formation is temporally coupled to resorption ensuring there is little net bone loss. However, this balance is disrupted in many skeletal disorders such as post-menopausal osteoporosis, breast and prostate cancer. Our work aims to understand the mechanisms leading to the disruption of bone cell activity and assess the beneficial impact of potential novel nutritional factors on tumour and bone cell function.
Inflammation is the cornerstone of innate immune defence against infection but may also cause tissue damage and pathology if not properly regulated. An example is sepsis, a clinical emergency that carries a high mortality. Sepsis is a consequence of disregulation of the inflammatory response. Moreover, inflammatory responses underlie a variety of diseases and chronically may trigger conditions such as atherosclerosis and neurodegeneration. Therefore, understanding the regulation of inflammation is key to developing effective treatments for sepsis and prevention of many disease states. Our group has been investigating how cells of the innate immune system respond to infectious stimuli to produce inflammatory mediators. We are elucidating these mechanisms to find targets for new anti-inflammatory therapies.
Throughout history most pathogens have been acquired by transmission from animal reservoirs (called a zoonotic infection). Ebola virus infection in humans (from chimpanzees and gorillas), and bovine tuberculosis infection in cattle (from badgers) are two examples of ongoing zoonotic diseases from wild animal populations. Vaccination of such animal populations in the wild is impossible using conventional approaches due to the need for inoculation of individual animals. An exciting new method we are testing is to insert regions from Ebola virus and TB into harmless viruses normally carried by these animals, and to use them as 'disseminating' vaccines that are able to spread through the entire population. This has the added value of also protecting the wild animals.
Membrane proteome dynamics
Current investigations of membrane proteome dynamics include (a) elucidation and function of membrane proteolysis in microorganisms using advanced protein turnover approaches are to discover new targets of membrane proteases and provide additional functional insight; (b) key events and players in sperm chemo-perception using targeted proteomics techniques to deliver stoichiometric information about signalling proteins and post-translational protein modifications. These projects are conducted within our proteomics group and in collaboration with partners elsewhere in the UK, and in Germany and Argentina.
Membrane protease function
New drug targets for malaria
Malaria is a global disease with about 1 million deaths each year caused by Plasmodium falciparum parasites. The life cycle of these parasites is very complex, where the parasite shuttles between human and mosquito host. Gametocytogenesis - the sexual development of parasites into male and female gametocytes - is essential for transmission of the parasite from human to mosquito host. It is considered as the Achilles heel of the malaria parasite, where we focus our research efforts on for establishing effective intervention strategies. Current work within our proteomics group involve the characterization of the proteins that are expressed at male and female gametocytes to find targets that are essential for sexual development and prevent parasite transmission from human to mosquito.
Understanding the cancer microenvironment
By employing a variety of approaches including molecular and cellular biology, immunology, omics, next-generation sequencing, bioinformatics, animal models, clinical tumour samples and relevant data, my research is dedicated to delineate mechanisms on how key molecules (such as microRNAs, lncRNAs, and RN181 E3 ligase), signalling pathways (such as Notch signalling), tumour cells, and tumour stromal cells (such as endothelial cells, infiltrating lymphocytes and tumour-associated macrophages) in tumour microenvironment regulate tumour growth, metastasis and tumour response to therapeutic interventions (cross-interactions among chemotherapy, targeted therapy and immunotherapy). Our aims are to dissect mechanisms of tumour growth and metastasis, develop novel therapeutic targets, and improve therapeutic efficacy by optimal combinations of chemotherapy, targeted therapy and immunotherapy.
The increased use of biodegradable synthetic or natural scaffolds combined with cells and/or biological molecules, in order to create functional replacement tissue in a damaged tissue site, has led to the need for the development of suitable biocompatible methods in the area of tissue engineering. This will inform and help create safe, high quality products for use both in vitro and in vivo. Numerous tools are now available to create 3D tissue models in vitro, but translating these effectively to clinical use has had limited success. Our work aims to develop culture systems for a variety of tissue types to promote assays for in vitro tissue modelling, and in particular for oral tissues and conditions.
Plugging the gaps in the antibiotic discovery pipeline
The WHO have declared that antibiotic resistance is one of the major threats to human health and the Chief Medical Officer recently raised this issue nationally. However, there is still a real need to discover novel antibiotics. Infections caused by drug resistant pathogens are a significant cause of morbidity and mortality and pan-resistant organisms are becoming less rare. My group runs a programme of natural product screening for discovery of bacteriocins, antimicrobial peptides produced by bacteria. The programme is supported by use of next generation sequencing methods to determine bacterial genome sequences and generate metagenomic datasets that can be interrogated with various software tools for identification of putative bacteriocins. Lead compounds are being developed towards clinical use with commercially focused funding from BBSRC and other sources.
Improving oral health
Periodontitis is a chronic inflammatory disease of the tissues supporting the teeth. My research interests include microbiology of periodontal diseases, host-pathogen interactions, Toll-Like Receptors signalling, immunopathogenesis of chronic inflammation and mechanisms involved in the resolution of inflammatory response (endotoxin tolerance). I am particularly interested in the chemical composition of Porphyromonas gingivalis LPS, modifications of its lipid-A structure, sialylation of O-specific polysaccharide chains and the consequences these changes have on the host immune response. Other areas of my research interest are molecular and cellular mechanisms responsible for tissue injury during inflammation, identification of therapeutic targets for resolution of inflammation and oral-systemic health connection.