Molecular mechanisms of Toll-like receptor 9 activation and the role of TLRs in autoimmunity

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The innate immune system has developed germ-line encoded pattern recognition receptors (PRR) that promote rapid responses to microbial pathogens. Toll-like receptors (TLRs) represent a newly recognized family of vertebrate PRR that activate and direct the anti-pathogen response through recognition of conserved pathogen associated molecular patterns (PAMP). TLR2 and TLR4 are the receptors for responses to gram-positive and gram-negative bacterial cell wall components such as lipopolysaccharide (LPS) or peptidoglycan. TLR9 has recently been identified as receptor for bacterial DNA, which acts as PAMP, similar to LPS. In contrast to LPS or peptidoglycan, bacterial DNA has to be taken up by an unknown sequence unspecific DNA receptor and endocytozed to activate the signaling pathway. TLR9 is localized in an endosomal / lysosmal vesicular structure and unpublished data suggest an unknown chaperone being responsible for the transport of newly synthesized TLR9 into this compartment. Aim of this project is to identify associated proteins of TLR9 which allow recognition of CpG-DNA. The identification and functional characterization of those co-receptors including knock-out studies in mice will help to understand the molecular mechanisms which are important for recognition of bacterial DNA and give insight into the anti pathogen response of the innate immune system.