Infection and Immunity

The Infection and Immunity arm of the Integrated Bioscience research group covers four main areas: Biofilms, Applied Microbiology and SynBio, Host-pathogen interactions, Immune responses and Treatment and diagnosis.

Infected cells

Microbial biofilms, Applied microbiology & Synthetic Biology

Microbial Biofilms

Progression of oral disease is often dependent upon the accumulation of oral plaque, a prime example of a bacterial biofilm. Biofilms are also important in several medical conditions, presenting a barrier to antibiotic treatment and contributing to the spread of antibiotic resistance traits. Methods to circumvent this recalcitrance to treatment are being studied, with the use of ultrasound as an intervention one example.

We are also interested in establishing the mechanisms involved in formation and progression of both mono- and mixed-species oral biofilms, with a specific focus on glycobiology of these organisms. Our focus is chiefly on biofilms of oral pathogens such as P. gingivalis and Tannerella forsythia that are major contributors to periodontitis, a disease affecting 200 million people worldwide that is associated with tooth loss and is increasingly considered as a risk factor for systemic diseases such as atherosclerosis. To enable these studies we occupy a suite of laboratories equipped with bacterial culture, molecular analysis and microscopy (including fluorescence microscopy and TEM) facilities in the dental school.  We also collaborate widely with the Dept of Molecular Biology and Biotechnology (Dr John Rafferty) on the structural biology of bacterial virulence enzymes.

Applied Microbiology and SynBio

In further work, with colleagues in the Department of Biomedical Science and the Kroto Institute we are investigating the use of novel compounds to treat biofilm infections and periodontal pathogens. A number of 'bug-binding' polymer have been developed that have potential applications in wound dressings and bacterial detection.
In addition, the group is working on a number of Synthetic Biology projects, including developing a number of bacterially derived chassis for the production of biomedically important proteins in E. coli for applications in Tissue engineering and biomedicine. This work is a collaboration with colleagues in Chemical and Biological Engineering (Dr Caroline Evans, and Prof P Wright at Newcastle, Dr Gillian Fraser in Cambridge and in collaboration with Fujifilm Diosynth Biotech).

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Host-pathogen interactions

The cellular microbiology research within the oral disease group examines the molecular mechanisms by which several pathogens interact with human cells. Our focus is upon both the immune response to bacterial challenge, particularly at the innate immune level, considering the influence of microRNAs and the glycobiology of pathogens in this process.  This site alongside work on the fundamental mechanisms of bacterial invasion into human cells. This is considered a mechanism by which micro-organisms might evade the host immune response. Understanding these key processes in infection is key to both understanding the disease process and, therefore to developing novel therapeutic strategies to prevent infection.

Our work focuses on investigation of interaction with epithelial cells (mucosal) and endothelial cells (blood vessels). Invasion of oral epithelial cells by periodontal pathogens, such as Porphyromonas gingivalis and Tannerella forsythia might be particularly important for their persistence in the mouth and for disease progression. We have also recently developed 3D-tissue and zebrafish models of infection for these pathogens to examine their role in disease.

Our recent work on periodontal pathogens addition uncovered a key role for sialic acid in the interaction of Tannerella forsythia with host glycoproteins and human cells in research conducted with collaborators at the University at Buffalo, USA and BOKU at Vienna, Austria. We also focus on the on the relationship between P. gingivalis gingipains with Integrin alpha 5 beta 1 and invasion capability in relation to cell cycle.

We are employing a range of microbiological and molecular techniques that utlilise our extensive cell-culture, fluorescence microscopy and molecular biology facilities. These include the use of  molecular tools (proteomics, transcriptomics, genomics) of invading bacteria and host cell responses.

Studies of endothelial cell interactions by Candida albicans are being developed under specially developed experimental conditions of flow which mimic the environment in the blood circulation. With collaborators strains where the virulence and morphogenesis of the Candida can be controlled are being studied under these flow conditions. In addition we are now i using zebrafish embryos as a model for Candidal infections.

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Immune responses

The mucosal immune system has developed to protect epithelial surfaces from micro-organisms and comprises both specific responses, controlled through lymphocyte activity, and non-specific defence, which has both cellular and soluble components.

One important component of this defence is provided by T lymphocytes, which are present in both the epithelium and underlying connective tissues and salivary glands. These lymphocytes are important in immune surveillance, particularly in defence against intra-cellular pathogens, malignant transformation and graft rejection. T lymphocytes also play a key role in the pathogenesis of a number of immune mediated inflammatory disorders and in the oral cavity these include lichen planus, erythema multiforme and Crohn´s disease.

The mechanisms used by these lymphocytes to recirculate through the oral mucosa are poorly understood and the specific role of chemokines and beta 7 integrins in this process are being investigated.

BPIF-containing proteins (formerly known as PLUNCs are a family of novel proteins, which were discovered and sequenced in Sheffield by members of the oral disease group ( L. Bingle). These proteins have structural similarity to lipopolysaccharide binding protein and so are thought to be important components of innate immunity. Recently BPIF proteins have been shown to be present in saliva and are differentially  expressed in different salivary glands. Their contribution to maintenance of oral health is currently being investigated.

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Treatment, diagnosis and monitoring in periodontal disease

Destruction of the periodontal tissues often results in tooth loss and is a major clinical problem. To improve patient-based diagnosis and evaluation of risk, members of the cluster are trying to identify genetic markers of increased susceptibility to periodontal disease. This is particularly targeted at examining gene polymorphisms in patients with the more severe forms of periodontal disease (Aggressive Periodontitis).

In order to more effectively target treatment, a biosensor is being developed for chair-side use to detect three key protease activities in gingival crevicular fluid, inlcuding human neutrophil elastase, a marker for periodontal inflammation. This work is being conducted in collaboration with Queen Mary College, London.

Concern over the widespread use of antimicrobials and the development of resistant strains has led to the search for alternative approaches to therapy. A multicentre clinical trial of photodynamic therapy is being conducted to determine its efficacy as a treatment for periodontal disease. Photodynamic therapy is based on the generation of reactive radicals from an activator in response to laser light.  In addition collaborative work with GSK is investigating new treatments for periodontal pathogens.

A multidisciplinary group (Chemistry, Oral & Maxillofacial Pathology, Engineering Materials) is developing a system for detecting infection in several body sites. Stimuli-responsive polymers are being devised with tethered ligands that bind directly to bacteria, or with peptides that can be cleaved by bacterial proteases, to detect the presence of bacteria or their products. This approach has numerous potential clinical applications, including early detection of wound infection.

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