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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.

SUBMITTER: Neufeldt CJ

PROVIDER: S-EPMC8755718 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Neufeldt Christopher J CJ Cerikan Berati B Cortese Mirko M Frankish Jamie J Lee Ji-Young JY Plociennikowska Agnieszka A Heigwer Florian F Prasad Vibhu V Joecks Sebastian S Burkart Sandy S SS Zander David Y DY Subramanian Baskaran B Gimi Rayomand R Padmanabhan Seetharamaiyer S Iyer Radhakrishnan R Gendarme Mathieu M El Debs Bachir B Halama Niels N Merle Uta U Boutros Michael M Binder Marco M Bartenschlager Ralf R

Communications biology 20220112 1

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 ...[more]

PMID: 35022513

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Project description:BackgroundThe immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in COVID-19 patients has been extensively investigated. However, much less is known about the long-term effects of infection in patients and how it could affect the immune system and its capacity to respond to future perturbations.MethodsUsing a targeted single-cell multiomics approach, we have recently identified a prolonged anti-inflammatory gene expression signature in T and NK cells in type 1 diabetes patients treated with low-dose IL-2. Here, we investigated the dynamics of this signature in three independent cohorts of COVID-19 patients: (i) the Oxford COVID-19 Multi-omics Blood Atlas (COMBAT) dataset, a cross-sectional cohort including 77 COVID-19 patients and ten healthy donors; (ii) the INCOV dataset, consisting of 525 samples taken from 209 COVID-19 patients during and after infection; and (iii) a longitudinal dataset consisting of 269 whole-blood samples taken from 139 COVID-19 patients followed for a period of up to 7 months after the onset of symptoms using a bulk transcriptomic approach.ResultsWe discovered that SARS-CoV-2 infection leads to a prolonged alteration of the gene expression profile of circulating T, B and NK cells and monocytes. Some of the genes affected were the same as those present in the IL-2-induced anti-inflammatory gene expression signature but were regulated in the opposite direction, implying a pro-inflammatory status. The altered transcriptional profile was detected in COVID-19 patients for at least 2 months after the onset of the disease symptoms but was not observed in response to influenza infection or sepsis. Gene network analysis suggested a central role for the transcriptional factor NF-κB in the regulation of the observed transcriptional alterations.ConclusionsSARS-CoV-2 infection causes a prolonged increase in the pro-inflammatory transcriptional status that could predispose post-acute patients to the development of long-term health consequences, including autoimmune disease, reactivation of other viruses and disruption of the host immune system-microbiome ecosystem.

Dataset Information

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

Publications

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

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