Topoisomerase II inhibitors induce DNA damage-dependent interferon responses circumventing ebola virus immune evasion

Priya Luthra, Sebastian Aguirre, Benjamin C. Yen, Colette A. Pietzsch, Maria T. Sanchez-Aparicio, Bersabeh Tigabu, Lorraine K. Morlock, Adolfo García-Sastre, Daisy W. Leung, Noelle S. Williams, Ana Fernandez-Sesma, Alexander Bukreyev, Christopher F. Basler

    Research output: Contribution to journalArticle

    20 Citations (Scopus)

    Abstract

    Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinasedependent manner and to also trigger the DNA-sensing c GAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication. IMPORTANCE Ebola virus and other emerging RNA viruses are significant but unpredictable public health threats. Therapeutic approaches with broad-spectrum activity could provide an attractive response to such infections. We describe a novel assay that can identify small molecules that overcome Ebola virus-encoded innate immune evasion mechanisms. This assay identified as hits cancer chemotherapeutic drugs, including doxorubicin. Follow-up studies provide new insight into how doxorubicin induces interferon (IFN) responses, revealing activation of both the DNA damage response kinase ATM and the DNA sensor c GAS and its partner signaling protein STING. The studies further demonstrate that the ATM and c GAS-STING pathways of IFN induction are a point of vulnerability not only for Ebola virus but for other RNA viruses as well, because viral innate immune antagonists consistently fail to block these signals. These studies thereby define a novel avenue for therapeutic intervention against emerging RNA viruses.

    Original languageEnglish (US)
    Article numbere00368-17
    JournalmBio
    Volume8
    Issue number2
    DOIs
    StatePublished - Mar 1 2017

    Fingerprint

    Ebolavirus
    Topoisomerase II Inhibitors
    Immune Evasion
    Interferons
    DNA Damage
    RNA Viruses
    Virus Replication
    Doxorubicin
    Interferon-beta
    Interferon-alpha
    Polynucleotide 5'-Hydroxyl-Kinase
    Pharmaceutical Preparations
    High-Throughput Screening Assays
    Intercalating Agents
    Type II DNA Topoisomerase
    Daunorubicin
    Anthracyclines
    DNA
    Proteins
    Therapeutics

    Keywords

    • ATM signaling
    • C GAS-STING pathway
    • DNA damage
    • Ebola virus
    • Innate immune responses

    ASJC Scopus subject areas

    • Microbiology
    • Virology

    Cite this

    Luthra, P., Aguirre, S., Yen, B. C., Pietzsch, C. A., Sanchez-Aparicio, M. T., Tigabu, B., ... Basler, C. F. (2017). Topoisomerase II inhibitors induce DNA damage-dependent interferon responses circumventing ebola virus immune evasion. mBio, 8(2), [e00368-17]. https://doi.org/10.1128/mBio.00368-17

    Topoisomerase II inhibitors induce DNA damage-dependent interferon responses circumventing ebola virus immune evasion. / Luthra, Priya; Aguirre, Sebastian; Yen, Benjamin C.; Pietzsch, Colette A.; Sanchez-Aparicio, Maria T.; Tigabu, Bersabeh; Morlock, Lorraine K.; García-Sastre, Adolfo; Leung, Daisy W.; Williams, Noelle S.; Fernandez-Sesma, Ana; Bukreyev, Alexander; Basler, Christopher F.

    In: mBio, Vol. 8, No. 2, e00368-17, 01.03.2017.

    Research output: Contribution to journalArticle

    Luthra, P, Aguirre, S, Yen, BC, Pietzsch, CA, Sanchez-Aparicio, MT, Tigabu, B, Morlock, LK, García-Sastre, A, Leung, DW, Williams, NS, Fernandez-Sesma, A, Bukreyev, A & Basler, CF 2017, 'Topoisomerase II inhibitors induce DNA damage-dependent interferon responses circumventing ebola virus immune evasion', mBio, vol. 8, no. 2, e00368-17. https://doi.org/10.1128/mBio.00368-17
    Luthra P, Aguirre S, Yen BC, Pietzsch CA, Sanchez-Aparicio MT, Tigabu B et al. Topoisomerase II inhibitors induce DNA damage-dependent interferon responses circumventing ebola virus immune evasion. mBio. 2017 Mar 1;8(2). e00368-17. https://doi.org/10.1128/mBio.00368-17
    Luthra, Priya ; Aguirre, Sebastian ; Yen, Benjamin C. ; Pietzsch, Colette A. ; Sanchez-Aparicio, Maria T. ; Tigabu, Bersabeh ; Morlock, Lorraine K. ; García-Sastre, Adolfo ; Leung, Daisy W. ; Williams, Noelle S. ; Fernandez-Sesma, Ana ; Bukreyev, Alexander ; Basler, Christopher F. / Topoisomerase II inhibitors induce DNA damage-dependent interferon responses circumventing ebola virus immune evasion. In: mBio. 2017 ; Vol. 8, No. 2.
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    abstract = "Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinasedependent manner and to also trigger the DNA-sensing c GAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication. IMPORTANCE Ebola virus and other emerging RNA viruses are significant but unpredictable public health threats. Therapeutic approaches with broad-spectrum activity could provide an attractive response to such infections. We describe a novel assay that can identify small molecules that overcome Ebola virus-encoded innate immune evasion mechanisms. This assay identified as hits cancer chemotherapeutic drugs, including doxorubicin. Follow-up studies provide new insight into how doxorubicin induces interferon (IFN) responses, revealing activation of both the DNA damage response kinase ATM and the DNA sensor c GAS and its partner signaling protein STING. The studies further demonstrate that the ATM and c GAS-STING pathways of IFN induction are a point of vulnerability not only for Ebola virus but for other RNA viruses as well, because viral innate immune antagonists consistently fail to block these signals. These studies thereby define a novel avenue for therapeutic intervention against emerging RNA viruses.",
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