Identification of a small molecule that primes the type I interferon response to cytosolic DNA
Abstract The type I interferon response plays a pivotal role in host defense against infectious agents and tumors, and promising therapeutic approaches rely on small molecules designed to boost this system. To identify such compounds, we developed a high-throughput screening assay based on HEK-293 c...
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Nature Portfolio
2017
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oai:doaj.org-article:ce16c14d2bc5493eb793e1d6481ee2552021-12-02T16:08:21ZIdentification of a small molecule that primes the type I interferon response to cytosolic DNA10.1038/s41598-017-02776-z2045-2322https://doaj.org/article/ce16c14d2bc5493eb793e1d6481ee2552017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02776-zhttps://doaj.org/toc/2045-2322Abstract The type I interferon response plays a pivotal role in host defense against infectious agents and tumors, and promising therapeutic approaches rely on small molecules designed to boost this system. To identify such compounds, we developed a high-throughput screening assay based on HEK-293 cells expressing luciferase under the control of Interferon-Stimulated Response Elements (ISRE). An original library of 10,000 synthetic compounds was screened, and we identified a series of 1H-benzimidazole-4-carboxamide compounds inducing the ISRE promoter sequence, specific cellular Interferon-Stimulated Genes (ISGs), and the phosphorylation of Interferon Regulatory Factor (IRF) 3. ISRE induction by ChX710, a prototypical member of this chemical series, was dependent on the adaptor MAVS and IRF1, but was IRF3 independent. Although it was unable to trigger type I IFN secretion per se, ChX710 efficiently primed cellular response to transfected plasmid DNA as assessed by potent synergistic effects on IFN-β secretion and ISG expression levels. This cellular response was dependent on STING, a key adaptor involved in the sensing of cytosolic DNA and immune activation by various pathogens, stress signals and tumorigenesis. Our results demonstrate that cellular response to cytosolic DNA can be boosted with a small molecule, and potential applications in antimicrobial and cancer therapies are discussed.Samira KhiarMarianne Lucas-HouraniSébastien NisoleNikaïa SmithOlivier HelynckMaryline BourgineClaude RuffiéJean-Philippe HerbeuvalHélène Munier-LehmannFrédéric TangyPierre-Olivier VidalainNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017) |
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Medicine R Science Q |
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Medicine R Science Q Samira Khiar Marianne Lucas-Hourani Sébastien Nisole Nikaïa Smith Olivier Helynck Maryline Bourgine Claude Ruffié Jean-Philippe Herbeuval Hélène Munier-Lehmann Frédéric Tangy Pierre-Olivier Vidalain Identification of a small molecule that primes the type I interferon response to cytosolic DNA |
| description |
Abstract The type I interferon response plays a pivotal role in host defense against infectious agents and tumors, and promising therapeutic approaches rely on small molecules designed to boost this system. To identify such compounds, we developed a high-throughput screening assay based on HEK-293 cells expressing luciferase under the control of Interferon-Stimulated Response Elements (ISRE). An original library of 10,000 synthetic compounds was screened, and we identified a series of 1H-benzimidazole-4-carboxamide compounds inducing the ISRE promoter sequence, specific cellular Interferon-Stimulated Genes (ISGs), and the phosphorylation of Interferon Regulatory Factor (IRF) 3. ISRE induction by ChX710, a prototypical member of this chemical series, was dependent on the adaptor MAVS and IRF1, but was IRF3 independent. Although it was unable to trigger type I IFN secretion per se, ChX710 efficiently primed cellular response to transfected plasmid DNA as assessed by potent synergistic effects on IFN-β secretion and ISG expression levels. This cellular response was dependent on STING, a key adaptor involved in the sensing of cytosolic DNA and immune activation by various pathogens, stress signals and tumorigenesis. Our results demonstrate that cellular response to cytosolic DNA can be boosted with a small molecule, and potential applications in antimicrobial and cancer therapies are discussed. |
| format |
article |
| author |
Samira Khiar Marianne Lucas-Hourani Sébastien Nisole Nikaïa Smith Olivier Helynck Maryline Bourgine Claude Ruffié Jean-Philippe Herbeuval Hélène Munier-Lehmann Frédéric Tangy Pierre-Olivier Vidalain |
| author_facet |
Samira Khiar Marianne Lucas-Hourani Sébastien Nisole Nikaïa Smith Olivier Helynck Maryline Bourgine Claude Ruffié Jean-Philippe Herbeuval Hélène Munier-Lehmann Frédéric Tangy Pierre-Olivier Vidalain |
| author_sort |
Samira Khiar |
| title |
Identification of a small molecule that primes the type I interferon response to cytosolic DNA |
| title_short |
Identification of a small molecule that primes the type I interferon response to cytosolic DNA |
| title_full |
Identification of a small molecule that primes the type I interferon response to cytosolic DNA |
| title_fullStr |
Identification of a small molecule that primes the type I interferon response to cytosolic DNA |
| title_full_unstemmed |
Identification of a small molecule that primes the type I interferon response to cytosolic DNA |
| title_sort |
identification of a small molecule that primes the type i interferon response to cytosolic dna |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/ce16c14d2bc5493eb793e1d6481ee255 |
| work_keys_str_mv |
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| _version_ |
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