title: Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation.
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.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Rialdi
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Campisi
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Arvin Cesar
authors.initials: AC
authors.lastname: Lagda
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Colette
authors.initials: C
authors.lastname: Pietzsch
authors.affiliation: Laboratory of Methyltransferases in Development and Disease, Institute of Molecular and Cell Biology, Singapore.
authors.forename: Jessica Sook Yuin
authors.initials: JSY
authors.lastname: Ho
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Department of Biochemistry and Molecular Biology, Universitat de Valencia, Valencia, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez-Gil
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Romain
authors.initials: R
authors.lastname: Fenouil
authors.affiliation: 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.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Edwards
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Giorgi
authors.initials: G
authors.lastname: Metreveli
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jordan
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Zuleyma
authors.initials: Z
authors.lastname: Peralta
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Cesar
authors.initials: C
authors.lastname: Munoz-Fontela
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bouvier
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: 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.
authors.forename: Matthew
authors.initials: M
authors.lastname: Weirauch
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.|Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Heinz
authors.affiliation: Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Harm
authors.initials: H
authors.lastname: van Bakel
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Basler
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bukreyev
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Marazzi
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use; D002166:Camptothecin / Q000494:pharmacology / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D029043:Ebolavirus; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics* / Q000382:microbiology; D009980:Influenza A virus; D016899:Interferon-beta / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D042925:Positive Transcriptional Elongation Factor B / Q000037:antagonists & inhibitors; D012319:RNA Polymerase II / Q000378:metabolism; D029082:Sendai virus; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019772:Topotecan / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D005419:Flavonoids; D010880:Piperidines; D059004:Topoisomerase I Inhibitors; D014230:Triazoles; C077990:alvocidib; D016899:Interferon-beta; D019772:Topotecan; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin