Shigellosis is one of the most serious cause of diarrheal disease in the world. The global impact has been estimated at over 160 million cases per year. Shigellosis is a major cause of infant mortality in developing countries with nearly 1 million deaths p er year.Shigella infiltrate and disrupt the integrity of the intestinal epithelium, initiate an inflammatory cascade, and induces apoptosis in host phagocytes. Adaptive immunity to Shigella infection is characterised by the induction of a humoral response. The duration of protection against re-infection is limited. The cellular immune response remains poorly understood. However, several data suggest that Shigella is able to manipulate the immune system to avoid the induction of a T-cell response. The specif ic aims of this project are to evaluate the CD4+ and CD8+ T-cell response during S. flexneri infection and to test the hypothesis that S. flexneri escape T-cell recognition by inducing apoptosis in T-lymphocytes.The first part includes a general analysis o f the T-cell response. The analysis will include mucosal T-cells and non-mucosal T-cells and will be performed in T-cells of the effector phase and the memory phase. Important aspects of the analysis are the induction, regulation, phenotype, and cytokine p rofile of Shigella-specific T-lymphocytes. Further experiments will investigate the T-cell dependence of protection against re-infection in different animal models.The second part of the project addresses the question whether S. flexneri induces T-cell kil ling by apoptosis. The specific aims are to analyse the effectiveness, the time-kinetics, and the possible mechanism of T-cell apoptosis induction. Strategies will be developed to test the hypothesis that T-lymphocytes apoptosis upon Shigella infection res ults in immune evasion leading to limited immunity to Shigella.
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