Nilsson-Payant BE, Uhl S, Grimont A, Doane AS, Cohen P, Patel RS, Higgins CA, Acklin JA, Bram Y, Chandar V, Blanco-Melo D, Panis M, Lim JK, Elemento O, Schwartz RE, Rosenberg BR, Chandwani R, tenOever BR
J Virol. 2021 Sep 15:JVI0125721 15/09/2021
PMID: 34523966
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 factors 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 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-κB for viral replication. IMPORTANCE 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 strains 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 in order to be able to develop novel approaches to target SARS-CoV-2 biology.