NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis.
NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis.
复制标题
DOI：
10.1371/journal.ppat.1000500
复制
发表时间：
2009-07
期刊：
影响因子：
6.7
通讯作者：
Kelliher MA
中科院分区：
文献类型：
--
作者：
Pandey AK;Yang Y;Jiang Z;Fortune SM;Coulombe F;Behr MA;Fitzgerald KA;Sassetti CM;Kelliher MA
虽然微生物感染的识别通常通过Toll样受体发生在细胞表面，但细胞的胞质溶胶也在监测破坏细胞膜的微生物产物。胞质识别的一个重要结果是诱导IFNα和IFNβ，它们是抗细菌和病毒免疫的关键介质。像许多细胞内病原体一样，结核分枝杆菌感染的转录反应的很大一部分取决于这些I型干扰素，但负责的识别途径仍然难以捉摸。在这项工作中，我们证明了吞噬体内M。结核病刺激响应细菌肽聚糖的胞质Nod 2途径，并且该事件需要由细菌主动造成的膜损伤。出乎意料的是，这种识别触发了Tbk 1和Irf 5依赖性方式的I型干扰素的表达。这种反应仅部分受到Irf 3损失的影响，因此与完全依赖于这种转录因子的细菌DNA刺激的反应根本不同。这种差异似乎是由分枝杆菌产生的不寻常的肽聚糖引起的，我们发现它是Nod 2/Rip 2/Irf 5途径的独特有效的激动剂。因此，Nod 2系统专门识别主动干扰宿主细胞膜的细菌，并且对分枝杆菌非常敏感，这可能反映了这些病原体对哺乳动物免疫系统施加的强大进化压力。细菌和病毒感染刺激几种细胞因子和趋化因子的产生，这些细胞因子和趋化因子被认为可以保护宿主免受感染。已知引起结核病的细菌菌株会刺激I型干扰素的产生，但尚不清楚细胞内分离的细菌如何能够刺激这种宿主反应。这项研究表明，细菌使用一种专门的系统来破坏这些细胞区室，并释放激活细胞内先天免疫途径的细菌产物。在这项工作中，我们证明了Nod 2，Rip 2，Tbk-1，Irf 3和Irf 5蛋白合作产生I型干扰素。了解这些途径是如何介导的可能有助于设计更有效的结核病疫苗。
While the recognition of microbial infection often occurs at the cell surface via Toll-like receptors, the cytosol of the cell is also under surveillance for microbial products that breach the cell membrane. An important outcome of cytosolic recognition is the induction of IFNα and IFNβ, which are critical mediators of immunity against both bacteria and viruses. Like many intracellular pathogens, a significant fraction of the transcriptional response to Mycobacterium tuberculosis infection depends on these type I interferons, but the recognition pathways responsible remain elusive. In this work, we demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway that responds to bacterial peptidoglycan, and this event requires membrane damage that is actively inflicted by the bacterium. Unexpectedly, this recognition triggers the expression of type I interferons in a Tbk1- and Irf5-dependent manner. This response is only partially impaired by the loss of Irf3 and therefore, differs fundamentally from those stimulated by bacterial DNA, which depend entirely on this transcription factor. This difference appears to result from the unusual peptidoglycan produced by mycobacteria, which we show is a uniquely potent agonist of the Nod2/Rip2/Irf5 pathway. Thus, the Nod2 system is specialized to recognize bacteria that actively perturb host membranes and is remarkably sensitive to mycobacteria, perhaps reflecting the strong evolutionary pressure exerted by these pathogens on the mammalian immune system. Bacterial and viral infection stimulates production of several cytokines and chemokines that are thought to protect the host against infection. The bacterial strain known to cause tuberculosis elicits production of type I interferons, yet it was unclear how the bacteria isolated within the cell was capable of stimulating this host response. This study reveals that the bacteria use a specialized system to cause damage to these cellular compartments and release bacterial products that activate intracellular innate immune pathways. In this work, we demonstrate that Nod2, Rip2, Tbk-1, Irf3 and Irf5 proteins cooperate to produce type I interferons. Understanding how these pathways are mediated is likely to aid in the design of more effective tuberculosis vaccines.
登录
查看更多内容
影响因子：
6.7
作者：
Geeraedts F;Goutagny N;Hornung V;Severa M;de Haan A;Pool J;Wilschut J;Fitzgerald KA;Huckriede A
通讯作者：
Huckriede A
DOI：
10.1016/0304-4165(70)90217-5
发表时间：
1970-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
AZUMA, I;THOMAS, DW;LEDERER, E
通讯作者：
LEDERER, E
影响因子：
3.2
作者：
Farrow, Mary F.;Rubin, Eric J.
通讯作者：
Rubin, Eric J.
影响因子：
11.8
作者：
Aziz, MA;Wright, A
通讯作者：
Wright, A
影响因子：
3.1
作者：
Gold, JA;Hoshino, Y;Weiden, MD
通讯作者：
Weiden, MD