TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation. Ho et al.

Published: 16 March 2021| Version 1 | DOI: 10.17632/myggxy4mmw.1
Contributor:
Jessica Ho

Description

Hyperinflammation that occurs during COVID19 is linked to increased disease severity and mortality. Reducing the magnitude of the inflammatory response during infection with SARS-CoV-2 might be key to the development of novel therapeutics against COVID19. We had previously shown that inhibition of epigenetic regulators such as Top1 can block lethal hyperinflammation associated with other models of bacterial and viral infections and co-infections. We first performed epigenetic characterization (Hi-C [table S1], H3K27ac ChIP Seq [table s2]) on A549-ACE2 cells infected with SARS-CoV-2 and identified a chromatin signature that is associated with SARS-CoV-2 infection. To then understand if Top1 is required for the inflammatory response against SARS-CoV-2, we performed RNA-sequencing in cells treated with control or TOP1 targeting siRNAs [table s3]. We found that genes associated with the inflammatory response are downregulated with TOP1 knockdown, suggesting that TOP1 is required for activating the inflammatory response in infected cells. Finally, we performed RNA-seq on the lungs of SARS-CoV-2 infected golden syrian hamsters that were treated either with DMSO vehicle control or topotecan (TPT), a TOP1 inhibitors [table s4]. We found that genes associated with the inflammatory response were down regulated in TPT treated hamsters. Histology scoring of the lungs of hamsters treated with TPT [table s5] also showed that these lungs were less inflammed. Taken together, our data suggest that TOP1 inhibition may be a suitable way to reduce inflammation in the context of SARS-CoV-2 infection.

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Detailed methods are outlined in the STAR methods section of our manuscript.