A dual-role of SARS-CoV-2 nucleocapsid protein in regulating innate immune response

Zhao, Yinghua; Sui, Liyan; Wu, Ping; Wang, Wenfang; Wang, Zedong; Yu, Yong; Hou, Zhijun; Tan, Guangyun; Liu, Quan; Wang, Guoqing

doi:10.1038/s41392-021-00742-w

Cited by 80 publications

(79 citation statements)

References 48 publications

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“…Recently, Zhao et al reported that the structural N protein may play a dual-role in regulating IFN signaling based on its expression level, i.e., the low-dose N protein was suppressive, while the high-dose was promotive, for the IFN response. This worked out by dually regulating the phosphorylation and nuclear translocation of IRF3, partially explaining how IFN signaling was activated [34]. As an alternative, our data provided an additional way for SARS-CoV-2 RNA virus to activate IFN response unexpectedly via cGAS-STING signaling pathway, which was secondary to the formation of multinucleate syncytia between cells expressing spike and ACE2.…”

Section: Discussionmentioning

confidence: 72%

Micronucleus production, activation of DNA damage response and cGAS-STING signaling in syncytia induced by SARS-CoV-2 infection

Ren

Peng

et al. 2021

Biol Direct

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SARS-CoV-2 infection could cause severe acute respiratory syndrome, largely attributed to dysregulated immune activation and extensive lung tissue damage. However, the underlying mechanisms are not fully understood. Here, we reported that viral infection could induce syncytia formation within cells expressing ACE2 and the SARS-CoV-2 spike protein, leading to the production of micronuclei with an average rate of about 4 per syncytium (> 93%). Remarkably, these micronuclei were manifested with a high level of activation of both DNA damage response and cGAS-STING signaling, as indicated by micronucleus translocation of γH2Ax and cGAS, and upregulation of their respective downstream target genes. Since activation of these signaling pathways were known to be associated with cellular catastrophe and aberrant immune activation, these findings help explain the pathological effects of SARS-CoV-2 infection at cellular and molecular levels, and provide novel potential targets for COVID-19 therapy.

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Section: Discussionmentioning

confidence: 72%

Micronucleus production, activation of DNA damage response and cGAS-STING signaling in syncytia induced by SARS-CoV-2 infection

Ren

Peng

et al. 2021

Biol Direct

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“…Many viruses that have co-evolved with their hosts have developed complex and multiple strategies to subvert or antagonize the host innate immune response as a mechanism to evade immune detection and elimination. Indeed, it has become increasingly clear that multiple SARS-CoV-2 encoded genes products target innate immune signaling pathways at various levels ( Xia et al., 2020 ; Fung et al., 2021 ; Han et al., 2021 ; Kumar et al., 2021 ; Sui et al., 2021a ; Vazquez et al., 2021 ; Zhao et al., 2021 ). Here we identify the Spike protein of SARS-CoV-2 as a key negative regulator of IFN-I activation in the RIG-I pathway that targets the IRF3 transcription factor and mediates its proteasomal degradation.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3

Freitas

Crum

Parvatiyar

2022

Front. Cell. Infect. Microbiol.

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Corona virus disease 2019 (COVID-19) pathogenesis is intimately linked to the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and disease severity has been associated with compromised induction of type I interferon (IFN-I) cytokines which coordinate the innate immune response to virus infections. Here we identified the SARS-CoV-2 encoded protein, Spike, as an inhibitor of IFN-I that antagonizes viral RNA pattern recognition receptor RIG-I signaling. Ectopic expression of SARS-CoV-2 Spike blocked RIG-I mediated activation of IFNβ and downstream induction of interferon stimulated genes. Consequently, SARS-CoV-2 Spike expressing cells harbored increased RNA viral burden compared to control cells. Co-immunoprecipitation experiments revealed SARS-CoV-2 Spike associated with interferon regulatory factor 3 (IRF3), a key transcription factor that governs IFN-I activation. Co-expression analysis via immunoassays further indicated Spike specifically suppressed IRF3 expression as NF-κB and STAT1 transcription factor levels remained intact. Further biochemical experiments uncovered SARS-CoV-2 Spike potentiated proteasomal degradation of IRF3, implicating a novel mechanism by which SARS-CoV-2 evades the host innate antiviral immune response to facilitate COVID-19 pathogenesis.

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“…Lethal pneumonia pathogenesis is usually associated with respiratory failure, resulting from cytokine storm-induced airway obstruction or alveolar epithelial damage [ 65 – 69 ]. We found that upregulated glycolysis, OXPHOS, glutathione metabolism, and sphingolipid metabolism may promote AT1 cell aging.…”

Section: Resultsmentioning

confidence: 99%

Cellular metabolic basis of altered immunity in the lungs of patients with COVID-19

Zhao

et al. 2022

Med Microbiol Immunol

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Metabolic pathways drive cellular behavior. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes lung tissue damage directly by targeting cells or indirectly by producing inflammatory cytokines. However, whether functional alterations are related to metabolic changes in lung cells after SARS-CoV-2 infection remains unknown. Here, we analyzed the lung single-nucleus RNA-sequencing (snRNA-seq) data of several deceased COVID-19 patients and focused on changes in transcripts associated with cellular metabolism. We observed upregulated glycolysis and oxidative phosphorylation in alveolar type 2 progenitor cells, which may block alveolar epithelial differentiation and surfactant secretion. Elevated inositol phosphate metabolism in airway progenitor cells may promote neutrophil infiltration and damage the lung barrier. Further, multiple metabolic alterations in the airway goblet cells are associated with impaired muco-ciliary clearance. Increased glycolysis, oxidative phosphorylation, and inositol phosphate metabolism not only enhance macrophage activation but also contribute to SARS-CoV-2 induced lung injury. The cytotoxicity of natural killer cells and CD8 + T cells may be enhanced by glycerolipid and inositol phosphate metabolism. Glycolytic activation in fibroblasts is related to myofibroblast differentiation and fibrogenesis. Glycolysis, oxidative phosphorylation, and glutathione metabolism may also boost the aging, apoptosis and proliferation of vascular smooth muscle cells, resulting in pulmonary arterial hypertension. In conclusion, this preliminary study revealed a possible cellular metabolic basis for the altered innate immunity, adaptive immunity, and niche cell function in the lung after SARS-CoV-2 infection. Therefore, patients with COVID-19 may benefit from therapeutic strategies targeting cellular metabolism in future. Supplementary Information The online version contains supplementary material available at 10.1007/s00430-021-00727-0.

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A dual-role of SARS-CoV-2 nucleocapsid protein in regulating innate immune response

Cited by 80 publications

References 48 publications

Micronucleus production, activation of DNA damage response and cGAS-STING signaling in syncytia induced by SARS-CoV-2 infection

Micronucleus production, activation of DNA damage response and cGAS-STING signaling in syncytia induced by SARS-CoV-2 infection

SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3

Cellular metabolic basis of altered immunity in the lungs of patients with COVID-19

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