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.
Highlights
SARS-CoV-2 is a novel virus that has rapidly spread, causing a global pandemic
In order to determine the effects of SARSCoV-2 on human lung epithelial cells, Calu-3 cells were infected with SARS-CoV-2 and the host transcriptional profiles were determined over the time course of infection
We report that both virus-induced transcriptional changes and cytokine profiles from two different infected epithelial cell lines are biased towards an inflammatory response, which is similar to the cytokine profiles observed in primary cells and with patient samples[2,3,4,5]
Summary
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; in a significant proportion of infections, individuals develop severe symptoms that can lead to long-lasting lung damage or death. Cytokine profiles from both severe COVID-19 patients and SARS-CoV-2 infected lung epithelial cells were enriched for pro-inflammatory cytokines, IL-6, and lacked type I/III IFNs. We demonstrate that SARS-CoV-2 infection leads to NF-κB, but not IRF3 nuclear localization, and that poly(I:C)-induced pathway activation is attenuated in infected cells. We show that the cGAS-STING pathway is activated by SARS-CoV-2 infection, leading to a specific NF-κB response and that inflammatory cytokine upregulation can be mitigated by several drugs that inhibit STING These results provide insight into how innate immune responses are modulated by SARS-CoV-2 in epithelial cells likely contributing to the initiation of the hyper-inflammatory responses observed in severe COVID-19 cases
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