TLR4 as an LPS sendor and susceptibility locus

TLR4 作为 LPS 发送者和易感基因座

基本信息

批准号：
7210572
负责人：
BRUCE A BEUTLER
金额：
$ 65.93万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-01 至 2009-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Using the germline mutagen N-ethyl-N-nitrosourea (ENU), we induced and then positionally cloned a mutation called Lps2. This mutation revealed that the mammalian LPS sensing pathway has two branches, one of which also forms the basis of an important viral sensing pathway. In brief, the dsRNA receptor (TLR3) and the LPS receptor (TLR4) utilize a common TIR adapter molecule, disrupted by the Lps2 mutation. Also known as Trif, or as Ticam-1, this adapter is essential for all MyD88-independentsignaling from both receptors, but does not transduce signals from the other TLRs. In vivo, the Trif Lps2/Lps2 genotype dramatically diminishes sensitivity to LPS, and increases susceptibility to infection by mCMV (and most probably many other viruses) by ablating the type I interferon response. We have shown that Trif, rather than MyD88, is of key importance in dendritic cell maturation, and by implication, in activation of the adaptive immune response as it occurs in the context of microbial infection. Moreover, we have ascertained the existence of Trif-dependent and Trif-independent macrophages, as well as poly I:C-responsive and poly I:C-unresponsive macrophages, and suggest that based on these phenotypic characteristics, macrophages must display afferent functional specificity. Our decipherment of TLR4 signaling pathways has thus raised many new questions to replace those that it has answered. We now propose to complete our phenotypic characterization of Lps2, to examine the functional specificity of macrophages with respect to signal transduction through the Trif axis, and also, to implement broadened phenotypic screens that will detect still other genes that influence responses to LPS and mCMV. The new mutations that are found--and those that have already been found in preliminary efforts--will be isolated by positional cloning.

描述（由申请人提供）：使用种系N-乙基n-硝化诱变（ENU），我们诱导然后定位克隆一个称为LPS2的突变。该突变表明，哺乳动物LPS感应途径有两个分支，其中一个分支也构成了重要的病毒传感途径的基础。简而言之，dsRNA受体（TLR3）和LPS受体（TLR4）利用了被LPS2突变破坏的常见TIR衔接子分子。该适配器也称为TRIF或TICAM-1，对于来自两个受体的所有myD88独立主注册都是必不可少的，但不会从其他TLR传输信号。在体内，TRIF LPS2/LPS2基因型大大降低了对LPS的敏感性，并通过消融I类肌膜反应来增加MCMV感染的敏感性。我们已经证明，Trif而不是MYD88在树突细胞的成熟中至关重要，并且暗示着在自适应免疫反应激活中，因为它在微生物感染的背景下发生。此外，我们已经确定了Trif依赖性和独立于TRIF的巨噬细胞的存在，以及Poly I：C-反应和Poly I：C-无反应巨噬细胞，并建议基于这些表型特征，巨噬细胞必须表现出传递的功能特异性。因此，我们对TLR4信号通路的解密提出了许多新问题，以取代它回答的问题。现在，我们建议完成LPS2的表型表征，以检查通过TRIF轴对信号转导的巨噬细胞的功能特异性，并实施扩大的表型筛选，这些筛选将检测其他基因，这些基因会影响对LPS和MCMV的反应。发现的新突变以及在初步努力中已经发现的突变 - 将通过位置克隆隔离。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evolution of the TIR, tolls and TLRs: functional inferences from computational biology.

DOI：
10.1007/978-3-642-59430-4_1
发表时间：
2002
期刊：
Current topics in microbiology and immunology
影响因子：
0
作者：
B. Beutler;M. Rehli
通讯作者：
B. Beutler;M. Rehli

The Tpl2 mutation Sluggish impairs type I IFN production and increases susceptibility to group B streptococcal disease.

Tpl2 突变缓慢会损害 I 型干扰素的产生并增加对 B 族链球菌疾病的易感性。

DOI：
10.4049/jimmunol.0902718
发表时间：
2009
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Xiao,Nengming;Eidenschenk,Celine;Krebs,Philippe;Brandl,Katharina;Blasius,AmandaL;Xia,Yu;Khovananth,Kevin;Smart,NoraG;Beutler,Bruce
通讯作者：
Beutler,Bruce

Genetic analysis of innate immunity: identification and function of the TIR adapter proteins.

先天免疫的遗传分析：TIR 接头蛋白的鉴定和功能。