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

Alex Rialdi, Laura Campisi, Nan Zhao, Arvin Cesar Lagda, Colette Pietzsch, Jessica Sook Yuin Ho, Luis Martinez-Gil, Romain Fenouil, Xiaoting Chen, Megan Edwards, Giorgi Metreveli, Stefan Jordan, Zuleyma Peralta, Cesar Munoz-Fontela, Nicole Bouvier, Miriam Merad, Jian Jin, Matthew Weirauch, Sven Heinz, Chris Benner & 5 others Harm Van Bakel, Christopher Basler, Adolfo García-Sastre, Alexander Bukreyev, Ivan Marazzi

    Research output: Contribution to journalArticle

    55 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Article number7993
    JournalScience
    Volume352
    Issue number6289
    DOIs
    StatePublished - May 27 2016

    Fingerprint

    Microbial Genes
    Ebolavirus
    Inflammation
    Gene Expression
    RNA Polymerase II
    Orthomyxoviridae
    Innate Immunity
    Genes
    Disease Progression
    Theoretical Models
    Pharmacology
    Therapeutics
    Infection

    ASJC Scopus subject areas

    • General
    • Medicine(all)

    Cite this

    Rialdi, A., Campisi, L., Zhao, N., Lagda, A. C., Pietzsch, C., Ho, J. S. Y., ... Marazzi, I. (2016). Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science, 352(6289), [7993]. https://doi.org/10.1126/science.aad7993

    Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. / Rialdi, Alex; Campisi, Laura; Zhao, Nan; Lagda, Arvin Cesar; Pietzsch, Colette; Ho, Jessica Sook Yuin; Martinez-Gil, Luis; Fenouil, Romain; Chen, Xiaoting; Edwards, Megan; Metreveli, Giorgi; Jordan, Stefan; Peralta, Zuleyma; Munoz-Fontela, Cesar; Bouvier, Nicole; Merad, Miriam; Jin, Jian; Weirauch, Matthew; Heinz, Sven; Benner, Chris; Van Bakel, Harm; Basler, Christopher; García-Sastre, Adolfo; Bukreyev, Alexander; Marazzi, Ivan.

    In: Science, Vol. 352, No. 6289, 7993, 27.05.2016.

    Research output: Contribution to journalArticle

    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 2016, 'Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation', Science, vol. 352, no. 6289, 7993. https://doi.org/10.1126/science.aad7993
    Rialdi A, Campisi L, Zhao N, Lagda AC, Pietzsch C, Ho JSY et al. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science. 2016 May 27;352(6289). 7993. https://doi.org/10.1126/science.aad7993
    Rialdi, Alex ; Campisi, Laura ; Zhao, Nan ; Lagda, Arvin Cesar ; Pietzsch, Colette ; Ho, Jessica Sook Yuin ; Martinez-Gil, Luis ; Fenouil, Romain ; Chen, Xiaoting ; Edwards, Megan ; Metreveli, Giorgi ; Jordan, Stefan ; Peralta, Zuleyma ; Munoz-Fontela, Cesar ; Bouvier, Nicole ; Merad, Miriam ; Jin, Jian ; Weirauch, Matthew ; Heinz, Sven ; Benner, Chris ; Van Bakel, Harm ; Basler, Christopher ; García-Sastre, Adolfo ; Bukreyev, Alexander ; Marazzi, Ivan. / Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. In: Science. 2016 ; Vol. 352, No. 6289.
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