Clostridium difficile is a nosocomial infection of increasing significance, mediated by secreted toxins A and B. Infection causes a spectrum of clinical disease varying from asymptomatic carriage to severe life-threatening pseudomembranous colitis. Despite adequate treatment, C. difficile-associated disease may recur in 15-35% of patients. Studies suggest that in addition to strain type, the host immune response to the secreted toxins may be important in determining not only the development of c linical disease but also its severity and risk of recurrence. The aim of the proposed research is to investigate the possible immune mechanisms underlying these clinical pictures. It is postulated that an impaired host humoral immune response to C. difficile toxins A and B is associated with severe and relapsing colonic disease. In novel studies, I intend to examine C. difficile toxin A- and B-specific B lymphocytes and antibody secreting cells in the circulation and colonic mucosa. Pl asma and faecal immunoglobulin levels will also be studied. These studies will be conducted in asymptomatic carriers as well as patients with mild, severe and relapsing disease. This research may facilitate the future development of effective vaccines and/or high-affinity recombinant human monoclonal antibodies for therapeutic purposes.

Meeting on Molecular Mechanisms and Manipulation in the Archaea, Nottingham The Nottingham meeting is needed to bring together major researchers based in the UK who are researching both the biochemistry and genetics of archaea. The opportunity for such an inter-disciplinary gathering of archaea researchers has not arisen previously; the meeting at Bath focussed on enzymology of DNA metabolism, at Nottingham we wish to encourage the inclusion of genetic approaches to research in this area. At least three of the labs attending (Shirley MacReady, Peter Lund and Thorsten Allers) are making advances in methodologies and applications of genetics in archaea, results that have not yet been aired in the wider research community. The meeting will seed collaborations that would be far more difficult to achieve remotely. Nottingham will also allow attendees to review the progress of existing collaborations in the enzymology of DNA replication and repair. We anticipate that the framework for a major research grant proposal will be forthcoming from the meeting.