Wagner Hermann
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Trogerstr. 30, München, Germany.
Curr Opin Immunol. 2008 Aug;20(4):396-400. doi: 10.1016/j.coi.2008.06.013. Epub 2008 Jul 30.
The prevailing paradigm ascribes activation of Toll-like receptor 9 (TLR9) to the detection of CpG-motifs within pathogen derived DNA. However, new work ties natural phospho-diester (PD) DNA recognition by TLR9 to the detection of the DNA sugar backbone 2' deoxyribose. PD 2' deoxyribose homopolymers lacking DNA bases (abasic) are shown to act as TLR9 agonist while abasic phospho-thioate (PS) 2' deoxyribose functions as TLR9 antagonist. Alignment of bases to PD 2' deoxyribose enhanced its TLR9 agonistic function, while only CpG-motifs introduced to inhibitory PS 2' deoxyribose converted the antagonistic activity into powerful agonistic function. These new data thus restrict the CpG-motif dependency of TLR9 activation to the promising group of immunopharmacons that are based on PS modified synthetic DNA. They also show that natural PD DNA drives TLR9 activation sequence-independently as is the case for ds RNA recognizing TLR3 and ss RNA recognizing TLR7 and TLR8. Thus evolutionary pressure might have exiled nucleic acid recognizing TLRs such as TLR9 to endosomes in order to avoid activation by host (self) derived nucleic acids.
目前的范式将Toll样受体9（TLR9）的激活归因于对病原体衍生DNA中CpG基序的检测。然而，新的研究将TLR9对天然磷酸二酯（PD）DNA的识别与DNA糖骨架2'-脱氧核糖的检测联系起来。缺乏DNA碱基（无碱基）的PD 2'-脱氧核糖均聚物被证明可作为TLR9激动剂，而无碱基的硫代磷酸酯（PS）2'-脱氧核糖则作为TLR9拮抗剂。碱基与PD 2'-脱氧核糖的比对增强了其TLR9激动功能，而仅引入到抑制性PS 2'-脱氧核糖中的CpG基序将拮抗活性转化为强大的激动功能。因此，这些新数据将TLR9激活对CpG基序的依赖性限制在基于PS修饰的合成DNA的有前景的免疫药物组中。它们还表明，天然PD DNA与识别双链RNA的TLR3以及识别单链RNA的TLR7和TLR8一样，以序列无关的方式驱动TLR9激活。因此，进化压力可能已将识别核酸的TLR（如TLR9）驱逐到内体中，以避免被宿主（自身）衍生的核酸激活。
