TY - JOUR
T1 - Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation
AU - Rialdi, Alex
AU - Campisi, Laura
AU - Zhao, Nan
AU - Lagda, Arvin Cesar
AU - Pietzsch, Colette
AU - Ho, Jessica Sook Yuin
AU - Martinez-Gil, Luis
AU - Fenouil, Romain
AU - Chen, Xiaoting
AU - Edwards, Megan
AU - Metreveli, Giorgi
AU - Jordan, Stefan
AU - Peralta, Zuleyma
AU - Munoz-Fontela, Cesar
AU - Bouvier, Nicole
AU - Merad, Miriam
AU - Jin, Jian
AU - Weirauch, Matthew
AU - Heinz, Sven
AU - Benner, Chris
AU - Van Bakel, Harm
AU - Basler, Christopher
AU - García-Sastre, Adolfo
AU - Bukreyev, Alexander
AU - Marazzi, Ivan
N1 - 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.
PY - 2016/5/27
Y1 - 2016/5/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84965071427&partnerID=8YFLogxK
U2 - 10.1126/science.aad7993
DO - 10.1126/science.aad7993
M3 - Article
C2 - 27127234
AN - SCOPUS:84965071427
SN - 0036-8075
VL - 352
JO - Science
JF - Science
IS - 6289
M1 - 7993
ER -