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Science. 2016 May 27;352(6289):aad7993. doi: 10.1126/science.aad7993. Epub 2016 Apr 28.

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

Author information

1
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Department of Pathology, Microbiology, and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
4
Laboratory of Methyltransferases in Development and Disease, Institute of Molecular and Cell Biology, Singapore.
5
Department of Biochemistry and Molecular Biology, Universitat de Valencia, Valencia, Spain.
6
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Center for Autoimmune Genomics and Etiology (CAGE) and Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
8
Department of Oncological Sciences, Tisch Cancer Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9
Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
10
Department of Structural and Chemical Biology, Department of Oncological Sciences, and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
11
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
12
Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
#
Contributed equally

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. 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.

PMID:
27127234
PMCID:
PMC5193222
DOI:
10.1126/science.aad7993
[Indexed for MEDLINE]
Free PMC Article

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