Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation.
Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation.
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DOI：
10.1126/science.aad7993
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发表时间：
2016-05-27
期刊：
影响因子：
--
通讯作者：
Marazzi I
中科院分区：
文献类型：
--
作者：
Rialdi A;Campisi L;Zhao N;Lagda AC;Pietzsch C;Ho JSY;Martinez-Gil L;Fenouil R;Chen X;Edwards M;Metreveli G;Jordan S;Peralta Z;Munoz-Fontela C;Bouvier N;Merad M;Jin J;Weirauch M;Heinz S;Benner C;van Bakel H;Basler C;García-Sastre A;Bukreyev A;Marazzi I
宿主的先天免疫反应是抵御病原体的第一道防线，是由微生物刺激诱导的基因协同表达而产生的。这些基因表达的失控与炎症加重相关疾病的发生和发展有关。我们发现拓扑异构酶1(Top1)是病原体诱导基因中RNA聚合酶II转录活性的正调控因子。Top1的耗尽或化学抑制会抑制宿主对流感和埃博拉病毒以及细菌产品的反应。Top1的治疗药理作用抑制在致死性炎症实验模型中保护小鼠免于死亡。我们的结果表明，Top1抑制物可用于治疗以免疫反应急剧加剧为特征的危及生命的感染。
The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. We identified topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against influenza and Ebola viruses as well as bacterial products. Therapeutic pharmacological inhibition of Top1 protected mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life-threatening infections characterized by an acutely exacerbated immune response.
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