Subproject B12

The immunology of Helicobacter pylori infection is a major focus of our research towards the development of a vaccine. It appears that T cells are of utmost importance for fighting this infection while B cells and antibodies are either obsolete of may have a pathological role. We recently discovered that cholesterol can modulate this infection in a T cell dependent way. H. pylori is a cholesterol auxotroph and seems to extract the required cholesterol from the membranes of host cells the bacteria attach to in the stomach mucosa. The cholesterol is subsequently metabolized and glucosid-derivatives are synthesised by bacterial enzymes. Extraction of cholesterol or the presence of its a glucosid derivatives inhibits phagocytosis of the bacteria by professional phagocytes. In contrast, the addition of exogenous cholesterol to bacteria exposed to phagocytes in vitro promotes their uptake, degradation and, in the case of antigen-presenting cells (APC), presentation of peptide epitopes to specific T cells. Moreover, a diet rich in cholesterol given to H. pylori infected mice led to a dramatic T cell dependent infiltration of leukocytes eventually resulting in a 100fold reduction of H. pylori organisms in the host stomach. Thus, H. pylori may evade immune recognition by a finely tuned mechanism involving cholesterol extraction and derivatization.

We now like to dissect the molecular mechanism of the cholesterol/cholesterol-α-glucoside mediated immunomodulation and investigate whether this modulation can be exploited for a novel immunotherapeutic strategy. We will analyse whether this modulation involves cholesterol/cholesterol-α-glucoside dependent interference with signalling cascades, with the phagocytic process and/or with antigen processing in APCs. In addition we will investigate whether other cell populations, such as T cells and in particular regulatory T cells are also affected by this process. These studies will be conducted using human cells and tissue explants as well as mouse cells and will draw on the possibilities offered by the mouse H. pylori infection model. Eventually this may help to devise more effective immunotherapies against this global health hazard.