SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB

Abstract

SARS-CoV-2 is a novel virus that has rapidly spread, causing a global pandemic. In the majority of infected patients, SARS-CoV-2 leads to mild disease; however, in a significant proportion of infections, individuals develop severe symptoms that can lead to permanent lung damage or death. These severe cases are often associated with high levels of pro-inflammatory cytokines and low antiviral responses which can lead to systemic complications. We have evaluated transcriptional and cytokine secretion profiles from infected cell cultures and detected a distinct upregulation of inflammatory cytokines that parallels samples taken from infected patients. Building on these observations, we found a specific activation of NF-κB and a block of IRF3 nuclear translocation in SARS-CoV-2 infected cells. This NF-κB response is mediated by cGAS-STING activation and could be attenuated through STING targeting drugs. Our results show that SARS-CoV-2 curates a cGAS-STING mediated NF-κB driven inflammatory immune response in epithelial cells that likely contributes to inflammatory responses seen in patients and might be a target to suppress severe disease symptoms.

Single-cell analyses reveal SARS-CoV-2 interference with intrinsic immune response in the human gut

“…The nature of the PRR responsible for sensing SARS-CoV-2 infection is yet to be determined but from recent work and previous work on SARS-CoV-1 and MERS it could be speculated that TLR3, RLRs and the STING pathways could be involved [39,40]. In our current work we could show that active virus replication is required to induce an IFN-mediated response as infection by UV-inactivated SARS-CoV-2 did not lead to IFN and ISG production (Fig.…”

NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients

“…Regarding the cell types affected, single cell transcriptome and phenotyping studies show that SARS-CoV-2-induced hyperactivation seems to affect a broad spectrum of cells ranging from epithelial cells of the respiratory tract (16)(17)(18), lining endothelial cells (6,7), cells of the innate immune system, including macrophages and mast cells located in the submucosa of the respiratory tract (15,19), and PBMC (including monocytes, dendritic cells, CD4-and CD8 T-cells) (13,15,20).…”

“…Key examples were TNF, NF-kB, IL-1, and ALOX5 signaling pathways (17). Several recent reports have demonstrated the NF-kB pathway as the central signaling pathway for the SARS-CoV-2 infection-induced proinflammatory cytokine/chemokine response (16)(17)(18)(35)(36)(37). Huang et al showed in a human in vitro model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2 a rapid transcriptomic change in infected cells, characterized by a shift to an inflammatory phenotype with upregulation of NF-kB signaling and NF-kB target genes by day 1 post-infection, followed by a loss of the mature alveolar program (16).…”

NF-kappaB pathway as a potential target for treatment of critical stage COVID-19 patients

“…Key examples were TNF, NF-kB, IL-1 and ALOX5 signaling pathways 28 . Several recent reports demonstrating NF-kB pathway as the central signaling pathway for the SARS-CoV-2 infection-induced pro-in ammatory cytokine/chemokine response 29,30 and show that COVID-19 upregulate toll-like receptor (TLR)-mediated in ammatory signaling mimicking bacterial sepsis 31 .…”