The nf-κ b transcriptional footprint is essential for sars-cov-2 replication

Benjamin E. Nilsson-Payant, Skyler Uhl, Adrien Grimont, Ashley S. Doane, Phillip Cohen, Roosheel S. Patel, Christina A. Higgins, Joshua A. Acklin, Yaron Bram, Vasuretha Chandar, Daniel Blanco-Melo, Maryline Panis, Jean K. Lim, Olivier Elemento, Robert E. Schwartz, Brad R. Rosenberg, Rohit Chandwani, Benjamin R. tenOever

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37 Scopus citations


SARS-CoV-2, the etiological agent of COVID-19, is characterized by a delay in type I interferon (IFN-I)-mediated antiviral defenses alongside robust cytokine production. Here, we investigate the underlying molecular basis for this imbalance and implicate virus-mediated activation of NF-κ B in the absence of other canonical IFN-I-related transcription factors. Epigenetic and single-cell transcriptomic analyses show a selective NF-κ B signature that was most prominent in infected cells. Disruption of NF-κ B signaling through the silencing of the NF-κ B transcription factor p65 or p50 resulted in loss of virus replication that was rescued upon reconstitution. These findings could be further corroborated with the use of NF-κ B inhibitors, which reduced SARS-CoV-2 replication in vitro. These data suggest that the robust cytokine production in response to SARS-CoV-2, despite a diminished IFN-I response, is the product of a dependency on NF-κ B for viral replication.

Original languageEnglish
Article numbere01257-21
JournalJournal of Virology
Issue number23
StatePublished - Dec 2021


  • NF-κ B
  • SARS-CoV-2


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