Details

Autor(en) / Beteiligte

• 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 B.R.
• 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

Titel

TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

Ist Teil von

• Cell, 2021-05, Vol.184 (10), p.2618-2632.e17

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •TOP1 activates inflammatory gene expression during SARS-CoV-2 infection•Topotecan (TPT), a TOP1 FDA-approved drug, suppresses inflammatory gene expression•Inflammatory genes suppressed by TPT are overexpressed in COVID-19 lung autopsies•TPT therapy protects from hyper-inflammation and death in preclinical models Inhibition of topoisomerase 1 through the FDA-approved molecule topotecan suppresses SARS-CoV-2-infection-associated lethal inflammation in hamster and mouse models without compromising antiviral immune responses.