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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