Pseudomonas aeruginosa has emerged as a major opportunistic pathogen during the past century. The invasion of host cells plays a fundamental role in the pathogenesis of this bacterium. As clinically important antibiotic resistance of P. aeruginosa continues to increase, the identification of host as well as microbial factors essential for P. aeruginosa uptake may lead to new drug targets.Our highly ambitious and interdisciplinary research project at the interface of biology, chemistry and physics aims at describing the molecular mechanism of the internalization of P. aeruginosa in non-phagocytic cells. Based on novel concepts that we have established for some bacterial toxins and animal viruses, we hypothesize that specific interactions of the P. aeruginosa lectins LecA and LecB with distinct glycosphingolipids exposed at the host cell surface lead to formation of plasma membrane invaginations, activation and recruitment of signaling molecules, cytoskeleton remodeling and cellular uptake of the bacterium. In order to acquire highly complementary results and to ensure the maximal outcome, we will perform our studies on diverse animal cells and various membrane model systems in combination with super resolution imaging techniques, biochemical and screening approaches. For the in vitro reconstitution of bacterial invasion, we will develop a unique platform for membrane nanoscopy based on planar pore-suspending membrane systems of different complexity (e.g. pore-suspending plasma membrane sheets and synthetic lipid bilayers). We expect to be able to identify key factors of bacterial uptake and small molecule inhibitors towards them in order to develop new therapies against the pathogenesis of P. aeruginosa infections.