Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation.

Abstract

The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. We identified topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against influenza and Ebola viruses as well as bacterial products. Therapeutic pharmacological inhibition of Top1 protected mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life-threatening infections characterized by an acutely exacerbated immune response.

• Authors: Alex Rialdi, Laura Campisi, Nan Zhao, Arvin Cesar Lagda, Colette Pietzsch, Jessica Sook Yuin Ho, Luis Martinez-Gil, Romain Fenouil, Xiaoting Chen, Megan Edwards, Giorgi Metreveli, Stefan Jordan, Zuleyma Peralta, Cesar Munoz-Fontela, Nicole Bouvier, Miriam Merad, Jian Jin, Matthew Weirauch, Sven Heinz, Chris Benner, Harm van Bakel, Christopher Basler, Adolfo García-Sastre, Alexander Bukreyev, Ivan Marazzi
• Journal: Science (New York, N.Y.) (Science) Vol. 352 Issue 6289 Pg. aad7993 (May 27 2016) ISSN: 1095-9203 [Electronic] United States
• PMID: 27127234 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• (+)-JQ1 compound
• Azepines
• Flavonoids
• Piperidines
• Topoisomerase I Inhibitors
• Triazoles
• alvocidib
• Interferon-beta
• Topotecan
• Positive Transcriptional Elongation Factor B
• RNA Polymerase II
• DNA Topoisomerases, Type I
• Camptothecin

Topics

• Animals
• Azepines (pharmacology, therapeutic use)
• Camptothecin (pharmacology, therapeutic use)
• DNA Topoisomerases, Type I (metabolism)
• Ebolavirus
• Flavonoids (pharmacology, therapeutic use)
• Gene Expression Regulation (drug effects)
• HEK293 Cells
• Hemorrhagic Fever, Ebola (drug therapy)
• Host-Pathogen Interactions (drug effects, genetics)
• Humans
• Immunity, Innate
• Inflammation (drug therapy, genetics, microbiology)
• Influenza A virus
• Interferon-beta (immunology)
• Mice
• Mice, Inbred C57BL
• Piperidines (pharmacology, therapeutic use)
• Positive Transcriptional Elongation Factor B (antagonists & inhibitors)
• RNA Polymerase II (metabolism)
• Sendai virus
• Staphylococcal Infections (drug therapy)
• Staphylococcus aureus
• Topoisomerase I Inhibitors (pharmacology, therapeutic use)
• Topotecan (therapeutic use)
• Transcription, Genetic (drug effects)
• Triazoles (pharmacology, therapeutic use)