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 long-lasting lung damage or death. These severe cases are often associated with high levels of pro-inflammatory cytokines and low antiviral responses, which can cause systemic complications. Here, we have evaluated transcriptional and cytokine secretion profiles and detected a distinct upregulation of inflammatory cytokines in infected cell cultures and 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 was mediated by cGAS-STING activation and could be attenuated through several STING-targeting drugs. Our results show that SARS-CoV-2 directs a cGAS-STING mediated, NF-κB-driven inflammatory immune response in human epithelial cells that likely contributes to inflammatory responses seen in patients and could be therapeutically targeted to suppress severe disease symptoms.

The cGAS–STING pathway drives type I IFN immunopathology in COVID-19

“… 26 ), endothelial cells in our LoC studies contain viral elements, arguing for direct viral involvement in triggering mitochondrial dysfunction and, in turn, the activity of the cGAS–STING pathway. Along these lines, cell-autonomous activation of cGAS–STING signalling has recently been suggested to contribute to the NF-κB-dependent production of cytokines in SARS-CoV-2-infected human epithelial cell lines 39 , which indicates that the pathway could have a more extensive role in COVID-19-associated cytokine responses. Given the importance of vascular damage in COVID-19, establishing the precise upstream cause (or causes) of endothelial cell involvement in viral activities is an area that warrants future investigation 21 , 40 .…”

Generation of human tonsil epithelial organoids as an ex vivo model for SARS-CoV-2 infection

“…To perform Gene Ontology (GO) analysis affected by SARS-CoV-2 infection, the virus was highly purified by ultracentrifugation, that removes secretory molecules, such as pro-inflammatory cytokines, existing in the viral stock [ 54 ]. We compared mRNA expression levels of 21,449 genes of the organoids from three donors (21-3, 21-4 and 20–23) at 3, 24, and 72 h after infection.…”

A New Butyrate Releaser Exerts a Protective Action against SARS-CoV-2 Infection in Human Intestine

“…It is known that SARS-CoV-2 infection triggers endoplasmic reticulum stress responses in the infected cells associated with reduced Nfr2 and increased levels of reactive oxygen species (ROS) [ 32 ]. These mechanisms trigged the “cytokine storm” through Nf-kB activation, a negative regulator of Nfr2 [ 32 , 33 , 34 ]. We found that FBA reduced Nf-kB activation and increased Nfr2 protein levels in human enterocytes exposed to WT SARS-CoV-2, leading to an antioxidant cellular state ( Figure 3 D).…”