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Comparison of gene expression in HeLa cells after treatment with IFN-b, IFN-g, or VPgEMCV.

ABSTRACT: We uncovered that cells infected with the encephalomyocarditis virus (EMCV) release soluble factors that induce apoptosis in uninfected cells. These factors were identified as the cytokine TNF-α and the viral protein VPgEMCV, which is necessary for viral RNA synthesis. Intriguingly, we discovered that VPgEMCV also acts as a functional mimic of IFN-γ, activating its canonical signaling pathway. This includes phosphorylation of STAT1 and the induction of IRF-1 and iNOS, leading to increased nitric oxide (NO) production. The synergy of NO accumulation and TNF-α signaling initiates powerful apoptosis. To compare gene sets regulated by IFN-I signaling (IFN-b), IFN-II signaling (IFN-g), and VPgEMCV signaling, we utilized RNA-seq analysis. From the deep sequencing data, we further discovered that VPgEMCV induces a gene expression profile similar to IFN-II signaling (IFN-γ), while also uniquely downregulating a distinct subset of genes. Our findings reveal that this cytokine-mimicry function of VPgEMCV regulates genes to control both viral replication and disease pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286568 | GEO | 2025/10/31

REPOSITORIES: GEO

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Project description:COVID-19 has rapidly circulated around the globe and caused significant morbidity and mortality. The disease is characterized by excessive production of pro-inflammatory cytokines and acute lung damage and patient mortality. Although initial cytokine cascades may be beneficial to the host for clearing the virus, enhanced production of pro-inflammatory cytokines and increasing levels in the systemic circulation, referred to as cytokine storm, can promote tissue damage by inducing inflammatory cell death in both infected and bystander cells. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combination of TNF-α and IFN-γ specifically induced cell death characterized by GSDME¬–mediated pyroptosis, caspase-8–mediated apoptosis, and MLKL–mediated necroptosis. Cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. However, deletion of pyroptosis, apoptosis, or necroptosis individually was not sufficient to protect against cell death. Mechanistically, the STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of inflammatory cell death protected mice from TNF-α and IFN-γ–induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. To determine the physiological relevance of protection, we neutralized both TNF-α and IFN-γ in multiple disease models associated with cytokine storm and found that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models. Collectively, our findings reveal that blocking the COVID-19 cytokine-mediated inflammatory cell death signaling pathway identified in this study may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancer where TNF-α and IFN-γ synergism play key pathological roles.

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Comparison of gene expression in HeLa cells after treatment with IFN-b, IFN-g, or VPgEMCV.

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