The DNA sugar backbone 2' deoxyribose determines toll-like receptor 9 activation |
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Authors: | Haas Tobias Metzger Jochen Schmitz Frank Heit Antje Müller Thomas Latz Eicke Wagner Hermann |
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Affiliation: | 1. Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Trogerstrasse 30, 81675 München, Germany;2. Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675 München, Germany;3. University of Massachusetts Medical School, Division of Infectious Diseases and Immunology, 364 Plantation Street, Worcester, MA 01605, USA |
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Abstract: | CpG motifs within phosphorothioate (PS)-modified DNA drive Toll-like receptor 9 (TLR9) activation, but the rules governing recognition of natural phosphodiester (PD) DNA are less understood. Here, we showed that the sugar backbone determined DNA recognition by TLR9. Homopolymeric, base-free PD 2' deoxyribose acted as a basal TLR9 agonist as it bound to and activated TLR9. This effect was enhanced by DNA bases, even short of CpG motifs. In contrast, PS-modified 2' deoxyribose homopolymers acted as TLR9 and TLR7 antagonists. They displayed high affinity to both TLRs and did not activate on their own, but they competitively inhibited ligand-TLR interaction and activation. Although addition of random DNA bases to the PS 2' deoxyribose backbone did not alter these effects, CpG motifs transformed TLR9-inhibitory to robust TLR9-stimulatory activity. Our results identified the PD 2' deoxyribose backbone as an important determinant of TLR9 activation by natural DNA, restrict CpG-motif dependency of TLR9 activation to synthetic PS-modified ligands, and define PS-modified 2' deoxyribose as a prime effector of TLR9 and TLR7 inhibition. |
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