The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.
|Publication status||Published - 13 May 2021|
We thank the staff of KSU Biosecurity Research Institute; the histological laboratory at the Kansas State Veterinary Diagnostic Laboratory (KSVDL); members of the Histology and Immunohistochemistry sections at the Louisiana Animal Disease Diagnostic Laboratory (LADDL); the CMG staff; and Bianca Artiaga, Dashzeveg Bold, Konner Cool, Emily Gilbert-Esparza, Chester McDowell, and Yonghai Li. We thank the teams at the Icahn School of Medicine at Mount Sinai, the Genomics and Mouse facilities, and Alan Soto from the Biorepository and Pathology Dean’s CoRE. We thank Cindy Beharry, Nanyi Julia Zhao, Nancy Francoeur, Nataly Fishman, Marion Dejosez, Thomas Zwaka, and Carles Martinez-Romero for their help and advice. Luis Martinez (Texas Biomedical Research Institute) and the Center for Therapeutic Antibody Development (CTAD) (Thomas Moran, Andy Duty, and Thomas Kraus) kindly provided the NP1C7C7 antibody.This work was partially supported through grants from NBAF Transition Funds and the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) under contract number HHSN 272201400006C to A.G.-S.; the Department of Homeland Security Center of Excellence for Emerging and Zoonotic Animal Diseases under grant HSHQDC-16-A-B0006 to J.A.R.; CRIP (Center for Research for Influenza Pathogenesis CEIRS, contract HHSN272201400008C ); supplements to NIAID grant U19AI135972 and DOD grant W81XWH-20-1-0270 ; the Defense Advanced Research Projects Agency ( HR0011-19-2-0020 ); and the JPB Foundation , the Open Philanthropy Project (research grant 2020-215611  ), and anonymous donors. S.Y. received funding from a Swiss National Foundation (SNF) Early Postdoc.Mobility fellowship ( P2GEP3_184202 ). This work was partially supported by funding to I. Marazzi., specifically the Burroughs Wellcome Fund (United States; 1017892 ), the Chan Zuckerberg Initiative (United States; 2018-191895 ), the Hirschl Young Investigator fellowship, and NIH grants U01AI150748 and R01AI143840 . Partial support by the AMP Core of the Center of Emerging and Zoonotic Infectious Diseases of the National Institutes of Health under award number P20GM130448 to J.R.
Publisher Copyright: © 2021 Elsevier Inc.