Attenuated Interferon and Proinflammatory Response in SARS-CoV-2–Infected Human Dendritic Cells Is Associated With Viral Antagonism of STAT1 Phosphorylation

Yang, Dong; Chu, Hin; Hou, Yuxin; Chai, Yue; Shuai, Huiping; Lee, Andrew Chak-Yiu; Zhang, Xi; Wang, Yixin; Hu, Bingjie; Huang, Xiner; Yuen, Terrence Tsz Tai; Cai, Jian; Zhou, Jie; Yuan, Shuofeng; Zhang, Anna Jinxia; Chan, Jasper Fuk Woo; Yuen, Kwok Yung

doi:10.1093/infdis/jiaa356

Cited by 172 publications

(243 citation statements)

References 45 publications

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“…IFN-I and Konno et al have described a larger, natural SARS-CoV-2 ORF3b variant (56 aa) with increased anti-IFN-I activity [47]. Yang et al found that the SARS-CoV-2 inhibition of STAT1 phosphorylation leads to the attenuation of the interferon-stimulated genes transcription in monocyte-derived dendritic cells and macrophages [49]. Perhaps SARS-CoV-2 NSP1 blocks STAT1 phosphorylation in a similar manner as SARS-CoV-1 NSP1 [39], contributing to the inhibition of interferon response.…”

Section: Inhibition Of Ifn Activity By Sars-cov-2mentioning

confidence: 99%

An aberrant STAT pathway is central to COVID-19

Matsuyama

Kubli

Yoshinaga³

et al. 2020

Cell Death Differ

243

275

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COVID-19 is caused by SARS-CoV-2 infection and characterized by diverse clinical symptoms. Type I interferon (IFN-I) production is impaired and severe cases lead to ARDS and widespread coagulopathy. We propose that COVID-19 pathophysiology is initiated by SARS-CoV-2 gene products, the NSP1 and ORF6 proteins, leading to a catastrophic cascade of failures. These viral components induce signal transducer and activator of transcription 1 (STAT1) dysfunction and compensatory hyperactivation of STAT3. In SARS-CoV-2-infected cells, a positive feedback loop established between STAT3 and plasminogen activator inhibitor-1 (PAI-1) may lead to an escalating cycle of activation in common with the interdependent signaling networks affected in COVID-19. Specifically, PAI-1 upregulation leads to coagulopathy characterized by intravascular thrombi. Overproduced PAI-1 binds to TLR4 on macrophages, inducing the secretion of proinflammatory cytokines and chemokines. The recruitment and subsequent activation of innate immune cells within an infected lung drives the destruction of lung architecture, which leads to the infection of regional endothelial cells and produces a hypoxic environment that further stimulates PAI-1 production. Acute lung injury also activates EGFR and leads to the phosphorylation of STAT3. COVID-19 patients' autopsies frequently exhibit diffuse alveolar damage (DAD) and increased hyaluronan (HA) production which also leads to higher levels of PAI-1. COVID-19 risk factors are consistent with this scenario, as PAI-1 levels are increased in hypertension, obesity, diabetes, cardiovascular diseases, and old age. We discuss the possibility of using various approved drugs, or drugs currently in clinical development, to treat COVID-19. This perspective suggests to enhance STAT1 activity and/or inhibit STAT3 functions for COVID-19 treatment. This might derail the escalating STAT3/PAI-1 cycle central to COVID-19.

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Section: Inhibition Of Ifn Activity By Sars-cov-2mentioning

confidence: 99%

An aberrant STAT pathway is central to COVID-19

Matsuyama

Kubli

Yoshinaga³

et al. 2020

Cell Death Differ

243

275

View full text Add to dashboard Cite

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“…During an in vitro experiment, Yang et al (178) found that, despite being permissive to infection by SARS-CoV-2, human monocyte-derived macrophages and dendritic cells are not able to effectively produce viral replicates. Despite their central role in pathogenesis, this may indicate that these cells are not important reservoirs for viruses.…”

Section: Innate Immune Responsementioning

confidence: 99%

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

et al. 2020

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Coronavirus Disease 2019 (COVID-19) has been classified as a global threat, affecting millions of people and killing thousands. It is caused by the SARS-CoV-2 virus, which emerged at the end of 2019 in Wuhan, China, quickly spreading worldwide. COVID-19 is a disease with symptoms that range from fever and breathing difficulty to acute respiratory distress and death, critically affecting older patients and people with previous comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and mainly spreads through the respiratory tract, which it then uses to reach several organs. The immune system of infected patients has been demonstrated to suffer important alterations, such as lymphopenia, exhausted lymphocytes, excessive amounts of inflammatory monocytes and macrophages, especially in the lungs, and cytokine storms, which may contribute to its severity and difficulty of establishing an effective treatment. Even though no specific treatment is currently available, several studies have been investigating potential therapeutic strategies, including the use of previously approved drugs and immunotherapy. In this context, this review addresses the interaction between SARS-CoV-2 and the patient's host immune system during infection, in addition to discussing the main immunopathological mechanisms involved in the development of the disease and potential new therapeutic approaches.

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“…However, these DCs release significantly higher levels of different chemokines (MIP1-a, CCL5 or RANTES, IP-10, and MCP-1) required to induce neutrophil, monocyte/macrophage, and T cell infiltration. Similarly, SARS-CoV2 infection in moDCs also shows no productive virus replication, no antiviral type I, II, and III IFN generation, and low pro-inflammatory cytokine production (Figure 4) [178]. However, SARS-CoV2 infected moDCs do not produce chemokines as produced upon SARS-CoV infection (Figure 4).…”

Section: Immunometabolic Reprogramming Among Dcs and Nk Cells Duringmentioning

confidence: 92%

How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?

Kumar

2020

International Reviews of Immunology

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SARS-CoV2 infection or COVID-19 has created panic around the world since its first origin in December 2019 in Wuhan city, China. The COVID-19 pandemic has infected more than 46.4 million people, with 1,199,727 deaths. The immune system plays a crucial role in the severity of COVID-19 and the development of pneumonia-induced acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Along with providing protection, both innate and T cell-based adaptive immune response dysregulate during severe SARS-CoV2 infection. This dysregulation is more pronounced in older population and patients with comorbidities (Diabetes, hypertension, obesity, other pulmonary and autoimmune diseases). However, COVID-19 patients develop protective antibodies (Abs) against SARS-CoV2, but they do not long for last. The induction of the immune response against the pathogen also requires metabolic energy that generates through the process of immunometabolism. The change in the metabolic stage of immune cells from homeostasis to an inflammatory or infectious environment is called immunometabolic reprogramming. The article describes the cellular immunology (macrophages, T cells, B cells, dendritic cells, NK cells and pulmonary epithelial cells (PEC) and vascular endothelial cells) and the associated immune response during COVID-19. Immunometabolism may serve as a cell-specific therapeutic approach to target COVID-19.

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Attenuated Interferon and Proinflammatory Response in SARS-CoV-2–Infected Human Dendritic Cells Is Associated With Viral Antagonism of STAT1 Phosphorylation

Cited by 172 publications

References 45 publications

An aberrant STAT pathway is central to COVID-19

An aberrant STAT pathway is central to COVID-19

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?

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