Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion
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-antag...
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American Society for Microbiology
2017-04-01
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doaj-0d1e8d9c8c1f41a59e338109c002d5752021-07-02T02:00:52ZengAmerican Society for MicrobiologymBio2150-75112017-04-0182e00368-1710.1128/mBio.00368-17Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune EvasionPriya LuthraSebastian AguirreBenjamin C. YenColette A. PietzschMaria T. Sanchez-AparicioBersabeh TigabuLorraine K. MorlockAdolfo García-SastreDaisy W. LeungNoelle S. WilliamsAna Fernandez-SesmaAlexander BukreyevChristopher F. BaslerTerence S. DermodyEbola 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.http://mbio.asm.org/cgi/content/full/8/2/e00368-17 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 Terence S. Dermody |
spellingShingle |
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 Terence S. Dermody Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion mBio |
author_facet |
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 Terence S. Dermody |
author_sort |
Priya Luthra |
title |
Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion |
title_short |
Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion |
title_full |
Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion |
title_fullStr |
Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion |
title_full_unstemmed |
Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion |
title_sort |
topoisomerase ii inhibitors induce dna damage-dependent interferon responses circumventing ebola virus immune evasion |
publisher |
American Society for Microbiology |
series |
mBio |
issn |
2150-7511 |
publishDate |
2017-04-01 |
description |
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. |
url |
http://mbio.asm.org/cgi/content/full/8/2/e00368-17 |
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