SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage

Sui, Yongjun; Li, Jianping; Venzon, David; Berzofsky, Jay A.

doi:10.3389/fimmu.2021.658428

Cited by 42 publications

(37 citation statements)

References 62 publications

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“…Consistent with our findings, it was recently reported that recombinant SARS-CoV-2 Spike protein, when incubated with primary cells from lung bronchoalveolar lavage from rhesus macaques, was able to suppress IFN-I levels ( Sui et al., 2021b ). Our data, in part, attempts to uncover the mechanism by which Spike suppresses the IFN-I response by revealing that SARS-CoV-2 Spike targets the IRF3 transcription factor.…”

Section: Discussionsupporting

confidence: 93%

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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Section: Discussionsupporting

confidence: 93%

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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“…Given the fact that SARS-CoV-1 and SARS-CoV-2 both rely on the binding of the viral S glycoprotein to ACE2 for viral entry into cells it was therefore highly likely that ACE2 would also be downregulated by SARS-CoV-2 in COVID-19. This has now been confirmed by Lei et al (2021) [31], Pedrosa et al (2021) [32] and Sui et al (2021) [33]. For example, Pedrosa et al (2021) showed that the S protein can cause a 50% reduction in the 120KDa membrane-bound form of ACE2 in human alveolar type 2 A549 cells.…”

Section: The Role Of Ace2 In the Raas And Kksmentioning

confidence: 74%

Role of the Renin–Angiotensin–Aldosterone and Kinin–Kallikrein Systems in the Cardiovascular Complications of COVID-19 and Long COVID

Cooper

Boyle

Jefferson

et al. 2021

IJMS

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. Patients may present as asymptomatic or demonstrate mild to severe and life-threatening symptoms. Although COVID-19 has a respiratory focus, there are major cardiovascular complications (CVCs) associated with infection. The reported CVCs include myocarditis, heart failure, arrhythmias, thromboembolism and blood pressure abnormalities. These occur, in part, because of dysregulation of the Renin–Angiotensin–Aldosterone System (RAAS) and Kinin–Kallikrein System (KKS). A major route by which SARS-CoV-2 gains cellular entry is via the docking of the viral spike (S) protein to the membrane-bound angiotensin converting enzyme 2 (ACE2). The roles of ACE2 within the cardiovascular and immune systems are vital to ensure homeostasis. The key routes for the development of CVCs and the recently described long COVID have been hypothesised as the direct consequences of the viral S protein/ACE2 axis, downregulation of ACE2 and the resulting damage inflicted by the immune response. Here, we review the impact of COVID-19 on the cardiovascular system, the mechanisms by which dysregulation of the RAAS and KKS can occur following virus infection and the future implications for pharmacological therapies.

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“…Although unmodified mRNA vaccines increase ISGs in both control and AGS samples, the internalization of the nucleoside modified mRNA vaccine representing the clinical vaccine significantly decreases ISGs relative to untreated samples in both control and AGS samples. It should be noted that the SARS-CoV-2 spike protein itself has been shown in vitro to result in decreased production of type 1 IFN [30], but that SARS-CoV-2 overall has a complex interaction with IFNs, likely associated with tissue specificity and disease severity [18, 29, 31]. It is promising that the expression of RNA sensing genes is upregulated only in the presence of unmodified mRNA vaccine, as expected.…”

Section: Discussionmentioning

confidence: 85%

mRNA-based vaccines against SARS-CoV-2 do not stimulate interferon stimulatory gene expression in individuals affected by Aicardi Goutières Syndrome

Takanohashi

Alameh

Woidill

et al. 2022

Preprint

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses threats to individuals with rare disease, in part because so little is known about the impact of COVID-19 infection and vaccination safety in rare disease populations. Of particular concern, given the overlap in disease manifestations and interferon dysregulation, are a group of heritable autoinflammatory conditions called type I interferonopathies. The most common of these, Aicardi Goutières Syndrome (AGS), is caused by altered nucleic acid metabolism and sensing, resulting in additional concerns surrounding the use of mRNA vaccination approaches. To determine whether mRNA vaccines induce an interferon response in AGS, we applied mRNA SARS-CoV-2 vaccines to whole blood samples and assessed internalization and interferon signaling gene expression responses to the mRNA. In all cases (11 AGS and 11 control samples), interferon signatures did not significantly increase from baseline, regardless of baricitinib treatment status in the AGS subjects, and were even decreased, when using codon optimized SARS-CoV-2 di-proline modified spike sequence (S2P). Internalization of S2P in human dendritic cells was verified by Western Blot, and in control and AGS blood cells was verified by Luciferase activity. Although numbers of tested samples in this rare disease are small, based on these findings, we suggest that COVID vaccination is unlikely to directly stimulate the interferon signaling gene expression in AGS patients via response to mRNA internalization. The in vitro nature of this study cannot exclude an exaggerated interferon response to spike protein production at a systemic level in individuals with a primary heritable interferonopathy. In the context of continued SARS-CoV-2 spread in the community, we do not recommend withholding vaccination in this rare disease group. However, we recommend that vaccinations for AGS patients are provided in a controlled setting with appropriate observation and used with caution in individuals with prior vaccine associated adverse events.

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SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage

Cited by 42 publications

References 62 publications

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

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

Role of the Renin–Angiotensin–Aldosterone and Kinin–Kallikrein Systems in the Cardiovascular Complications of COVID-19 and Long COVID

mRNA-based vaccines against SARS-CoV-2 do not stimulate interferon stimulatory gene expression in individuals affected by Aicardi Goutières Syndrome

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