2. Academic Validation
  3. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation

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

  • Science. 2016 May 27;352(6289):aad7993. doi: 10.1126/science.aad7993.
Alex Rialdi # 1 2,  Laura Campisi # 1 2,  Nan Zhao 1 2,  Arvin Cesar Lagda 1 2,  Colette Pietzsch 3,  Jessica Sook Yuin Ho 4,  Luis Martinez-Gil 1 5,  Romain Fenouil 6,  Xiaoting Chen 7,  Megan Edwards 1,  Giorgi Metreveli 1 2,  Stefan Jordan 8,  Zuleyma Peralta 6,  Cesar Munoz-Fontela 9,  Nicole Bouvier 1,  Miriam Merad 8,  Jian Jin 10,  Matthew Weirauch 7,  Sven Heinz 11 12,  Chris Benner 12,  Harm van Bakel 6,  Christopher Basler 1,  Adolfo García-Sastre 1 2,  Alexander Bukreyev 3,  Ivan Marazzi 1 2
Affiliations

Affiliations

  • 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.
PMID: 27127234 DOI: 10.1126/science.aad7993
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.

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