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• W338103984 abstract "The innate immune system consists of several pattern recognition receptors (PRRs), which recognize invading microorganisms by specific pathogen associated molecular patterns (PAMPs). Toll-like receptors (TLRs) are an important group of PRRs. To date, thirteen mammalian TLRs have been identified. TLRs are type I transmembrane receptors with a pathogen binding ectodomain (ECD) consisting of leucine-rich repeats (LRRs) and a cytoplasmic signaling domain, known as the toll/interleukin-1 receptor (TIR) domain. The TLR ECDs consist of a solenoid with 19-25 LRRs bent into a horseshoe shape. Certain LRRs are followed by insertions of amino acid sequences, which have been implicated in the recognition of PAMPs by TLRs. TLR9 is a receptor for DNA and synthetic oligodeoxynucleotides, and interacts with its ligand in endosomal compartments. We introduce a novel TLR9 agonist, which is able to override species-specific recognition of CpG motifs by TLR9. The agonist is shown to activate TLR9 from various species to induce an immune response. Moreover, it has been suggested that TLR9 is cleaved in the endosomes to yield a functional receptor. This cleavage of the receptor deletes the N-terminal part of the receptor, creating a functional receptor consisting of only the C terminal ECD. However, less is known about the function of the N-terminal domain of the receptor. We identified an important role for cysteine rich regions in the insert following LRR8 in the N-terminal TLR9 ECD for the induction of an immune response. TLR9 protein with specific mutations from cysteine to alanine in these motifs lost the ability to induce an immune response upon activation with a TLR9 agonist. The mutated proteins were able to bind ligand, but confocal imaging revealed the mutant proteins unable to translocate from the ER to ligand-containing compartments. This defect in trafficking was shown to be due to a decreased ability of mutant TLR9 to bind the transport protein UNC93B1. These results suggest that the N-terminal part of the TLR9 ECD plays a critical role in the normal cellular responses to its ligands. By doing a broad analysis of genes induced by a TLR9 agonist in wild type C57Bl6, Tlr9-/- and Myd88-/- myeloid dendritic cells (mDCs) we identified the antiviral gene viperin to be highly induced. In addition, we found that the transcription factor interferon regulatory factor (IRF) 5, and not IRF7, was central for TLR9 agonist induction of type I interferon (IFN) and viperin in mDCs. Furthermore, we identified a novel and important role for IRF5 in the in vivo antiviral response to murine cytomegalovirus (MCMV) infection. Irf5-/- mice showed a higher susceptibility to MCMV infection compared to wild type control mice. Irf5-/-mice displayed a higher viral titer in the spleen, increased liver pathology and decreased serum levels of proinflammatory cytokines and IFNs. The results presented in this thesis improve our general understanding of TLR9 and its activation by natural and synthetic ligands to induce an immune response. Our results may contribute to the design of future vaccine adjuvants, cancer treatments and anti-viral therapies directed against CMV infections." @default.
• W338103984 created "2016-06-24" @default.
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• W338103984 date "2010-01-01" @default.
• W338103984 modified "2023-09-25" @default.
• W338103984 title "Mechanisms of Toll-like Receptor 9 Activation" @default.
• W338103984 hasPublicationYear "2010" @default.
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