Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion
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 kinase-dependent manner and to also trigger the DNA-sensing cGAS-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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 03, 2017
- Source ID
- 10.1128/mbio.00368-17
Entities
People
- Adolfo García-Sastre
- Alexander Bukreyev
- Ana Fernández-Sesma
- Benjamin C. Yen
- Bersabeh Tigabu
- Christopher F Basler
- Colette A. Pietzsch
- Daisy W Leung
- Lorraine K. Morlock
- Maria T. Sanchez-aparicio
- Noelle S. Williams
- Priya Luthra
- Sebastian Aguirre
Organizations
- Georgia State University
- Icahn School of Medicine at Mount Sinai
- National Institutes of Health
- United States Department of Defense
- University of Texas Medical Branch
- University of Texas Southwestern Medical Center
- Washington University School of Medicine