Research Article

Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation

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Science  28 Apr 2016:
aad7993
DOI: 10.1126/science.aad7993

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Abstract

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. Here, we identify Topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II (RNAPII) 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. As a result, therapeutic pharmacological inhibition of Top1 protects 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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