Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection
Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection
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DOI：
10.1073/pnas.0400525101
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发表时间：
2004-03-09
影响因子：
11.1
通讯作者：
Beutler, B
中科院分区：
文献类型：
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作者：
Tabeta, K;Georgel, P;Beutler, B
树突状细胞的几个亚群已被证明产生I型干扰素，以响应病毒感染，从而协助自然杀伤细胞依赖性反应，消除病原体。I型IFN的产生可以由未甲基化的CpG-寡脱氧核苷酸和双链RNA诱导。在这里，我们描述了一个共显性的CpG-ODN无反应表型，从N-乙基-N-亚硝基脲诱导的错义突变Tlr 9基因（Tlr 9（CpG 1））的结果。Tlr 9（CpG 1）等位基因纯合子小鼠对小鼠巨细胞病毒感染高度易感，并显示感染诱导的IFN-α/β分泌和自然杀伤细胞活化受损。我们还证明了Toll样受体（TLR）9 -> MyD 88和TLR 3-> Trif信号通路在体内病毒接种时被激活，并且每个通路都有助于对系统性病毒感染的先天防御。尽管这两种途径都导致I型IFN的产生，但在缺乏另一种途径的情况下，两种途径都不能提供针对小鼠巨细胞病毒感染的完全保护。Tlr 9（CpG 1）突变改变了富含亮氨酸的重复基序，并且位于包含TLR 7、8和9的进化簇内保守的受体结构域内。在其他TLR中，包括本文中描述的三种小鼠特异性TLR，未显示受影响的区域。因此，Tlr（9 CpG 1）等位基因的表型效应指出了TLR 9在病毒传感中的关键作用，并鉴定了三种TLR蛋白质的胞外域内的易受攻击的氨基酸，其对于配体应答是必需的。
Several subsets of dendritic cells have been shown to produce type I IFN in response to viral infections, thereby assisting the natural killer cell-dependent response that eliminates the pathogen. Type I IFN production can be induced both by unmethylated CpG-oligode-oxynucleotide and by double-stranded RNA. Here, we describe a codominant CpG-ODN unresponsive phenotype that results from an N-ethyl-N-nitrosourea-induced missense mutation in the Tlr9 gene (Tlr9(CpG1)). Mice homozygous for the Tlr9(CpG1) allele are highly susceptible to mouse cytomegalovirus infection and show impaired infection-induced secretion of IFN-alpha/beta and natural killer cell activation. We also demonstrate that both the Toll-like receptor (TLR) 9 --> MyD88 and TLR3 --> Trif signaling pathways are activated in vivo on viral inoculation, and that each pathway contributes to innate defense against systemic viral infection. Whereas both pathways lead to type I IFN production, neither pathway offers full protection against mouse cytomegalovirus infection in the absence of the other. The Tlr9(CpG1) mutation alters a leucine-rich repeat motif and lies within a receptor domain that is conserved within the evolutionary cluster encompassing TLRs 7, 8, and 9. In other TLRs, including three mouse-specific TLRs described in this paper, the affected region is not represented. The phenotypic effect of the Tlr(9CpG1) allele thus points to a critical role for TLR9 in viral sensing and identifies a vulnerable amino acid within the ectodomain of three TLR proteins, essential for a ligand response.