@article{b6c66156bff2491d805d684cccb93b24,
title = "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.",
author = "Alex Rialdi and Laura Campisi and Nan Zhao and Lagda, {Arvin Cesar} and Colette Pietzsch and Ho, {Jessica Sook Yuin} and Luis Martinez-Gil and Romain Fenouil and Xiaoting Chen and Megan Edwards and Giorgi Metreveli and Stefan Jordan and Zuleyma Peralta and Cesar Munoz-Fontela and Nicole Bouvier and Miriam Merad and Jian Jin and Matthew Weirauch and Sven Heinz and Chris Benner and {Van Bakel}, Harm and Christopher Basler and Adolfo Garc{\'i}a-Sastre and Alexander Bukreyev and Ivan Marazzi",
note = "Funding Information: We thank P. Palese for the FF-luciferase construct, chromatized cells, and Sendai virus; F. Kramer for the H3N2 virus; R. Cadagan for help with virus propagations; T. Kraus for use of the Luminex 100/200 plate reader; M. Schotsaert for help with co-infection experiments; S. Tripathi for providing IRF3 dependency data; the genomics facility at Icahn School of Medicine at Mount Sinai; Bioproximity LLC for proteomics work; J. K. Gregory for help with computer graphics; and H. Nakano for discussion about the history of Top1 inhibitors. I. Marazzi and M. Byun designed the graphical abstract illustration of the {"}the Vitruvian automaton{"}; the illustration is our homage to Marcus Vitruvius Pollio, Leonardo da Vinci, and the history of automata. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. Sequencing data are available in GEO, GSE80132, and linked superseries. Supported by HHSN272201400008C-Center for Research on Influenza Pathogenesis (CRIP), a Center of Excellence for Influenza Research and Surveillance (CEIRS) funded by the National Institute of Allergy and Infectious Diseases (A.G.-S., G.M., H.v.B., and I.M.); Public Health Service Institutional Research Training Award AI07647 (A.R.); Department of Defense grant W911NF-14-1-0353 (I.M.); NIH grants U19AI106754 (I.M. and A.G.-S.), 1R01AN3663134 (I.M. and H.v.B.), U19AI109945 (A.B. and C. Basler), U19AI109664 (A.B. and C. Basler), and1R56AI114770-01A1 (I.M.); and the computational resources and staff of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. A patent application (62/267,608) was filed by Mount Sinai related to treatment of inflammatory diseases with Top1 inhibitors.",
year = "2016",
month = may,
day = "27",
doi = "10.1126/science.aad7993",
language = "English (US)",
volume = "352",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6289",
}