...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nucleic Acid Therapeutics >Dual or Triple Activation of TLR7, TLR8, and/or TLR9 by Single-Stranded Oligoribonucleotides
【24h】

Dual or Triple Activation of TLR7, TLR8, and/or TLR9 by Single-Stranded Oligoribonucleotides

机译：单链寡核糖核苷酸对TLR7，TLR8和/或TLR9的双重或三次激活

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The toll-like receptors (TLRs) 7, 8, and 9 stimulate innate immune responses upon recognizing pathogen nucleic acids. Certain GU- or AU-rich RNA sequences were described to differentiate between human TLR7- and TLR8-mediated immune effects. Those single-stranded RNA molecules require endosomal delivery for stabilization against ribonucleases. We have discovered RNA sequences that preferentially activate TLR7, form higher ordered structures, and do not require specific cellular delivery. In addition, a dual activation of TLR8 and TLR9 without affecting TLR7 can be achieved by chimeric molecules consisting of GU-rich RNA and Cytosin (C) phosphordiester or phosphorthioat (p) guanine (CpG) motif DNA sequences. Such chimeras stimulate TLR9-mediated type I interferon (IFN) and TLR8-depending proinflammatory cytokine and chemokine production upon primary human cell activation. However, an RNA-dependent TLR7 IFN-alpha cytokine release is suppressed by the phosphorothioate DNA sequence contained in the chimeric molecule. To convert the immune response of a single-stranded RNA from TLR7/8 to TLR9, a simple chemical modification at the 5' end proves to be sufficient. Such 8-oxo-2'-deoxy-guanosine or 8-bromo-2'-deoxy-guanosine modifications of the first guanosine in GU-rich single-stranded RNAs convert the immune response to include TLR9 activation and demonstrate strong additive effects for type I IFN immune responses in human primary cells.
机译：识别病原体核酸后，toll​​样受体（TLR）7、8和9会刺激先天免疫应答。描述了某些富含GU或AU的RNA序列，以区分人TLR7和TLR8介导的免疫效果。这些单链RNA分子需要内体递送以稳定抵抗核糖核酸酶。我们发现了优先激活TLR7，形成更高序结构且不需要特定细胞递送的RNA序列。此外，可以通过由富含GU的RNA和胞嘧啶（C）磷酸二酯或硫代磷酸酯（p）鸟嘌呤（CpG）基序DNA序列组成的嵌合分子实现TLR8和TLR9的双重激活而不会影响TLR7。此类嵌合体在原代人细胞激活后会刺激TLR9介导的I型干扰素（IFN）和TLR8依赖性促炎细胞因子和趋化因子的产生。但是，嵌合分子中包含的硫代磷酸酯DNA序列抑制了RNA依赖性TLR7IFN-α细胞因子的释放。为了将单链RNA的免疫应答从TLR7 / 8转换为TLR9，在5'端进行简单的化学修饰就足够了。富含GU的单链RNA中第一个鸟苷的此类8-oxo-2'-脱氧-鸟苷或8-bromo-2'-脱氧-鸟苷修饰将免疫应答转换为包括TLR9激活并显示出对2型糖尿病的强加和作用人原代细胞中的IFN免疫应答。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号