SARS-CoV-2 nsp12 attenuates type I interferon production by inhibiting IRF3 nuclear translocation

Wang, Wenjing; Zhou, Zhuo; Xiao, Xia; Tian, Zhongqin; Dong, Xuan; Wang, Conghui; Li, Li; Ren, Lili; Lei, Xiaobo; Zou, Xiang; Wang, Jianwei

doi:10.1038/s41423-020-00619-y

Cited by 115 publications

(110 citation statements)

References 42 publications

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“…Also, Nsp12, Nsp14, ORF3 and M proteins produced more than 50% inhibition of IFN-I induction after RIG-I overexpression [ 20 ]. However, subsequent studies generated contradictory results about the inhibitory activity of Nsp12 against IFN production and signaling [ 24 , 25 ], indicating that luciferase-based assays may be misleading [ 24 ]. The M protein was shown to impair IFN-I promoter activation by interfering with the prion-like aggregation of MAVS and its association with SNX8, thus disrupting the recruitment of the downstream components TRAF3, TBK-1 and IRF3 to the MAVS complex [ 26 ].…”

Section: In Vitro Inhibition Of the Ifn-i System By Sars-cov-2mentioning

confidence: 99%

Type I Interferons in COVID-19 Pathogenesis

Palermo

Carlo

Sgarbanti

et al. 2021

Biology

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Among the many activities attributed to the type I interferon (IFN) multigene family, their roles as mediators of the antiviral immune response have emerged as important components of the host response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Viruses likewise have evolved multiple immune evasion strategies to circumvent the host immune response and promote virus propagation and dissemination. Therefore, a thorough characterization of host–virus interactions is essential to understand SARS-CoV-2 pathogenesis. Here, we summarize the virus-mediated evasion of the IFN responses and the viral functions involved, the genetic basis of IFN production in SARS-CoV-2 infection and the progress of clinical trials designed to utilize type I IFN as a potential therapeutic tool.

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Section: In Vitro Inhibition Of the Ifn-i System By Sars-cov-2mentioning

confidence: 99%

Type I Interferons in COVID-19 Pathogenesis

Palermo

Carlo

Sgarbanti

et al. 2021

Biology

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“…8 – 10 It is reported that the recruitment of Th17 cells and increased IL-17 caused cytokine storm, and type I IFN response exacerbated inflammation in severe COVID-19 cases. 11 – 13 However, the underlying mechanism of cytokine storm in COVID-19 remains unclear.…”

Section: Introductionmentioning

confidence: 99%

CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta, alpha, beta, and gamma

Geng

Chen

Yuan

et al. 2021

Sig Transduct Target Ther

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SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants—alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 μg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a “spike protein-CD147-CyPA signaling axis”: Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.

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“…Importantly, the IFN-I/λ response is now thought to be a critical host response against SARS- CoV-2 infection and its pathogenesis (Grajales-Reyes and Colonna, 2020; Hadjadj et al, 2020; Kim and Shin, 2021; Sa Ribero et al, 2020; Saichi et al, 2021; Trouillet-Assant et al, 2020) . Recent studies have shown that SARS-CoV-2 can evade from this initial control by the IFN-I/λ response via manifold inhibitory mechanisms interfering with both the sensing and the signaling pathways within infected cells (reviewed in (Kim and Shin, 2021; Min et al, 2021; Park and Iwasaki, 2020; Sa Ribero et al, 2020) ), and e.g., illustrated in (Kimura et al, 2021; Lei et al, 2020; Miorin et al, 2020; Saichi et al, 2021 ; Wang et al, 2021; Xia et al, 2020) ). This immune evasion might lead to an increased viral load, followed by widespread inflammations (Sa Ribero et al, 2020) .…”

Section: Introductionmentioning

confidence: 99%

Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2-infected cells

Venet

Ribeiro

Décembre

et al. 2021

Preprint

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Type I and III interferons (IFN-I/λ) are key antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that the plasmacytoid dendritic cells (pDCs) are predominant IFN-I/λ source by sensing SARS-CoV-2-infected cells. We show that sensing of viral RNA by pDCs requires sustained cell adhesion with infected cells. In turn, the pDCs restrict viral spread by a local IFN-I/λ response directed toward SARS-CoV-2-infected cells. This specialized function enables pDCs to efficiently turn-off viral replication, likely by a concentrated flux of antiviral effectors at the contact site with infected cells. Therefore, we propose that pDC activation is essential to locally control SARS-CoV-2-infection. By exploring the pDC response in patients, we further demonstrate that pDC responsiveness correlates with the severity of the disease and in particular that it is impaired in severe COVID-19 patients. Thus, the ability of pDCs to respond to SARS-CoV-2-infected cells could be a key to understand severe cases of COVID-19.

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SARS-CoV-2 nsp12 attenuates type I interferon production by inhibiting IRF3 nuclear translocation

Cited by 115 publications

References 42 publications

Type I Interferons in COVID-19 Pathogenesis

Type I Interferons in COVID-19 Pathogenesis

CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta, alpha, beta, and gamma

Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2-infected cells

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