Identification of essential genes and receptors for the signaling of TLR2-dependent bacterial virulence factors (lipopeptides, peptidoglycan and lipoteichoic acid)

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The recognition of bacterial virulence factors by the innate immune system is the first step in mounting an adequate immune response that eventually will clear the host from the invading pathogen. The molecular basis for this recognition has just recently started to be understood. Components of Gram-negative and -positive bacteria cell walls, such as lipopolysaccharides (LPS), lipopeptides/lipoproteins (LP), peptidoglycan (PG), and lipoteichoic acid (LTA) are very potent activators of innate immune responses. Their main target cells are monocytes and the primary host recognition of some of these components is mediated through CD14. However, recent data show obvious differences between the mediating signaling receptors and pathways of LPS and LP/PG/LTA. Whereas LPS-responsive cells express Toll-like receptor (TLR) 4, LP/PG/LTA require the expression of TLR2. Furthermore, data are emerging that clearly favor the engagement of multimeric receptor complexes by bacterial pathogens. This project will focus on investigating the recognition and signaling of the TLR2-dependent bacterial virulence factors LP/PG/LTA. The aims of this project are 1) the identification and characterization of so far unknown genes that are essential for the signaling of LP/PG/LTA and 2) the analysis of the receptor complexes mediating LP/PG/LTA recognition.