The NF-κB 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
Author Information
Benjamin E Nilsson-Payant: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA. ORCID
Skyler Uhl: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA. ORCID
Adrien Grimont: Department of Surgery, Weill Cornell Medicinegrid.471410.7, New York, New York, USA. ORCID
Ashley S Doane: Department of Physiology and Biophysics, Weill Cornell Medicinegrid.471410.7, New York, New York, USA. ORCID
Phillip Cohen: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA. ORCID
Roosheel S Patel: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA. ORCID
Christina A Higgins: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA. ORCID
Joshua A Acklin: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA. ORCID
Yaron Bram: Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicinegrid.471410.7, New York, New York, USA. ORCID
Vasuretha Chandar: Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicinegrid.471410.7, New York, New York, USA. ORCID
Daniel Blanco-Melo: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA. ORCID
Maryline Panis: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA.
Jean K Lim: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA.
Olivier Elemento: Department of Physiology and Biophysics, Weill Cornell Medicinegrid.471410.7, New York, New York, USA. ORCID
Robert E Schwartz: Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicinegrid.471410.7, New York, New York, USA. ORCID
Brad R Rosenberg: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA. ORCID
Rohit Chandwani: Department of Surgery, Weill Cornell Medicinegrid.471410.7, New York, New York, USA. ORCID
Benjamin R tenOever: Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA. ORCID
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-κB in the absence of other canonical IFN-I-related transcription factors. Epigenetic and single-cell transcriptomic analyses show a selective NF-κB signature that was most prominent in infected cells. Disruption of NF-κB signaling through the silencing of the NF-κB 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-κB inhibitors, which reduced SARS-CoV-2 replication . 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-κB for viral replication. The COVID-19 pandemic has caused significant mortality and morbidity around the world. Although effective vaccines have been developed, large parts of the world remain unvaccinated while new SARS-CoV-2 variants keep emerging. Furthermore, despite extensive efforts and large-scale drug screenings, no fully effective antiviral treatment options have been discovered yet. Therefore, it is of the utmost importance to gain a better understanding of essential factors driving SARS-CoV-2 replication to be able to develop novel approaches to target SARS-CoV-2 biology.
