Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models
Author:
Yuin Ho Jessica Sook, Wing-Yee Mok Bobo, 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, Junxia Zhang Anna, Chak-Yiu Lee Andrew, Liu Wen-Chun, Aydillo TeresaORCID, Salom Melo Betsaida, Guccione Ernesto, Sebra Robert, Shum Elaine, Bakker Jan, Kaufman David A., Moreira Andre L., Carossino Mariano, Balasuriya Udeni B R, Byun Minji, Miraldi Emily R, Albrecht Randy A, Schotsaert Michael, Garcia-Sastre Adolfo, Chanda Sumit K, Jeyasekharan Anand DORCID, TenOever Benjamin R, Spivakov Mikhail, Weirauch Matthew T, Heinz SvenORCID, Chen Honglin, Benner Christopher, Richt Juergen A, Marazzi Ivan
Abstract
SUMMARYThe 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), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four 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 COVID-19 in humans.
Publisher
Cold Spring Harbor Laboratory
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