Research Interests
Bacterial sensing and manipulation of the host response
Discovering the mechanism of bacterial modification to changing environments will uncover new modalities for treatment, so we are investigating the interaction with, adhesion to, and sensing of surfaces (biotic and abiotic) by bacteria, using the polar and lateral flagella systems and type IV pili of Aeromonasspp as model systems (Dr Jonathon Shaw). Microbial pathogens secrete a range of molecules which have the potential to interact with the host. We therefore study surface-exposed and secreted proteins, some with no sequence homologues in the databases. Amongst others, the Gly1 and IgA1 protease of Neisseria meningitidis and the ComH protein of Helicobacter pylori are being investigated (Prof Jon Sayers).
Regulation of gene expression in bacterial pathogens and DNA Repair
The key to understanding bacterial adaptation is the definition of mechanisms of bacterial gene regulation and gene repair, chiefly in response to environmental stress and mutagens. Some of our work focuses on identifying virulence genes and investigating their regulation in members of the Gram-negative genus Burkholderia, particularly B. cenocepacia and B. pseudomallei. We are particularly interested in mechanisms of transcription regulation by activator proteins and ECF sigma factors in these bacteria (Dr Mark Thomas). To investigate DNA repair and replication, we are using site-directed mutagenesis, crystallography and kinetic studies to study flap endonuclease function. We are also studying a number of nucleases from bacteria, including the human pathogens Staphylococcus aureus and Helicabacter pylori (Prof Jon Sayers).
Subversion of innate immune defences by pathogens
Bacteria are able to colonise and invade humans because they can resist and in some cases manipulate innate defences. We have studied the influence on host-pathogen interactions of a number of bacterial virulence determinants including the nitric oxide reductase of N. meningitidis and the flavohaemoglobin Hmp of Salmonella enterica. This includes resistance to macrophage phagocytosis and killing, and persistence within the nasopharyngeal mucosa (Prof Robert Read and Prof David Dockrell). Furthermore, we are examining the role of bacterial glycosylation of extracellular virulence determinants, such as flagella, and their interaction with the immune system (Dr Jonathon Shaw). In addition, we are investigating the role of bacterial physiology in the virulence of N. meningitidis and N. gonorrhoeae (Dr Jonathon Shaw). The role of the Type VI secretion system in the interaction of pathogenic bacteria with host cells is also under investigation (Dr Jonathon Shaw and Dr Mark Thomas). Pneumonia remains a major cause of mortality, with increasing antibiotic resistance and evidence that excessive host immune responses result in poor clinical outcome. This has prompted us to investigate in detail, using a range of models, Streptococcus pneumoniae. This includes bacterial manipulation of phagolysosomal maturation, proinflammatory cytokine gene activation and apoptosis pathways (Prof David Dockrell and Prof Robert Read). The effect of viruses such as HIV-1 and Influenza A on phagocytes and lymphocytes are also examined (Prof David Dockrell).
Novel adjuvantation of vaccines and vaccinology
There is a strong track record of work on novel vaccine adjuvants based on stumulating lymphocytes through surface antigens such as CD40. This has been applied to HIV, HSV and pneumococcal vaccines and is currently being applied to influenza vaccines, TB vaccines for immuncompromised hosts and to potential lymphoma vaccines (Heath). There are ongoing projects on the mechanisms controlling B cell haematopoiesis (Heath) and on B cell/T cell cognate interactions during processing of protein-carbohydrate molecular complexes (Prof Robert Read and Prof Andrew Heath).
Clinical Research
Work is underway to examine the mechanisms of failure to seroconvert to the conjugate meningococcal vaccine (Prof Robert Read and Prof Andrew Heath). An experimental human challenge model using nasal inoculation of Neisseria lactamica is being developed in order to study mucosal immunity and Neisseria colonisation. In addition, clinical trials of novel meningococcal and influenza vaccines are conducted as well as clinical trials of novel treatments for HIV (Dockrell and Read). Operational research to optimise uptake and monitoring of highly active antiretroviral therapy to patients with HIV infection in resource-poor settings is also underway (Collini).
Genetics of Infectious Disease
Coordinate with research into the contribution of innate immunity to host defence, there is a major interest in human gene variation and its influence upon susceptibility to meningococcal disease. Genes of interest have included those encoding TNF, IL1, TLRs, and the collectins (Prof Robert Read).
Biotechnology and Commercial
We have developed techniques for genetic engineering, virulence gene identification and directed evolution and seek to apply them to biotechnology (Prof Jon Sayers, Dr Jonathon Shaw, Dr Mark Thomas). A University of Sheffield spin-out company, Asterion Limited, was founded in 2001 to develop novel proteins with potential for therapeutic use in man (Prof Jon Sayers). Another company, Adjuvantix Ltd, has been set up to exploit discoveries relating to CD40 and CD28 based vaccine adjuvants (Prof Andrew Heath).
Teaching
Members of the Unit lead and contribute to undergraduate teaching of medical students (MBChB and BMedSci) in Medical Microbiology and Infectious Disease components within all phases of the curriculum. In addition there is a major contribution to masters courses run within the School of Medicine and Research Training Programme modules.