학술논문
TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation.
Document Type
article
Author
Ho, Jessica Sook Yuin; Mok, Bobo Wing-Yee; Campisi, Laura; Jordan, Tristan; Yildiz, Soner; Parameswaran, Sreeja; Wayman, Joseph A; Gaudreault, Natasha N; Meekins, David A; Indran, Sabarish V; Morozov, Igor; Trujillo, Jessie D; Fstkchyan, Yesai S; Rathnasinghe, Raveen; Zhu, Zeyu; Zheng, Simin; Zhao, Nan; White, Kris; Ray-Jones, Helen; Malysheva, Valeriya; Thiecke, Michiel J; Lau, Siu-Ying; Liu, Honglian; Zhang, Anna Junxia; Lee, Andrew Chak-Yiu; Liu, Wen-Chun; Jangra, Sonia; Escalera, Alba; Aydillo, Teresa; Melo, Betsaida Salom; Guccione, Ernesto; Sebra, Robert; Shum, Elaine; Bakker, Jan; Kaufman, David A; Moreira, Andre L; Carossino, Mariano; Balasuriya, Udeni BR; Byun, Minji; Albrecht, Randy A; Schotsaert, Michael; Garcia-Sastre, Adolfo; Chanda, Sumit K; Miraldi, Emily R; Jeyasekharan, Anand D; TenOever, Benjamin R; Spivakov, Mikhail; Weirauch, Matthew T; Heinz, Sven; Chen, Honglin; Benner, Christopher; Richt, Juergen A; Marazzi, Ivan
Source
Cell. 184(10)
Subject
Language
Abstract
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.