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Cellular Microbiology
This group is investigating how micro-organisms interact with host cells and matrices. Initial studies of Aggregatibacter actinomycetemcomitans [Aa] , a key micro-organism responsible for localised aggressive periodontitis, identified chaperonin (Cpn) 60 as the major molecular chaperone (BBSRC project grant, ARC programme and project grants, 2 BHF project grants and an MRC industrial collaborative studentship). The group has been instrumental in identifying a tripartite toxin, "cytoskeletal distending toxin of Aa", and its mechanism of uptake into host cells, showing that it stimulates monocytes to make pro-inflammatory cytokines and also that it also promotes bone damage (funding from BBSRC, MRC, EPSRC/MRC). Other bacterial-host cell interactions deduced have included the mechanism of action and 3-dimensional structure (by nuclear magnetic resonance) of Aa resuscitation promoting factor (Rpf) . This led to studies of other Rpf-like proteins and we are currently examining homologues in other bacteria (Campylobacter jejuni and Salmonella typhimurium). Allied to the research of the Biofilms and ecology group, this group have identified key bacterial adhesins of orally (and systemically) relevant bacteria - specifically a novel family of fibronectin-binding proteins in the Pasteurellaceae (which includes Aa). Such fibronectin-binding proteins are also able to bind bacterial DNA, and may be environmental sensors important in controlling bacterial transformation, in which bacteria take up DNA from the environment. The group have also established that staphylococci can invade non-phagocytic cells, a process that involves the bacterial fibronectin-binding proteins, and that intracellular staphylococci are protected from antimicrobial therapy and the host immune defences. Sustainable research of the role of molecular chaperones in bacteria-host interactions has determined that Cpn60 from E. coli and humans directly stimulates osteoclast formation and can activate human monocytes to generate pro-inflammatory cytokines. The group also established that one Cpn60 protein of Mycobacterium tuberculosis can be a potent inhibitor of osteoclastogenesis (a second is not) and can inhibit bone destruction in animal models of arthritis and also inhibits experimental asthma. The clinical therapeutic potential of this chaperonin is being explored with Helperby Therapeutics. The group have also established that human Cpn60 is present in the blood circulation, that its levels correlate with measures of psychological distress and, in a large cohort of individuals with diabetes, with measures of coronary vascular disease. Further work has shown that the appearance of Hsp60 (heat shock protein) in the circulation of apparently healthy children is actually correlated with vascular dysfunction.
3 Researchers
  • Genetics, Evolution & Environment
  • Microbial Diseases
  • Dept of Biochemical Engineering
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