scholarly journals Severe Acute Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Production by Impeding the Formation of TRAF3·TANK·TBK1/IKKϵ Complex

2009 ◽  
Vol 284 (24) ◽  
pp. 16202-16209 ◽  
Author(s):  
Kam-Leung Siu ◽  
Kin-Hang Kok ◽  
Ming-Him James Ng ◽  
Vincent K. M. Poon ◽  
Kwok-Yung Yuen ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Transcriptional Activity ◽  
Type I Interferons ◽  
M Protein ◽  
Type I ◽  
Sars Coronavirus ◽  
Front Line ◽  
Highly Pathogenic ◽  
Double Stranded Rna ◽  
Multiple Levels

Severe acute respiratory syndrome (SARS) coronavirus is highly pathogenic in humans and evades innate immunity at multiple levels. It has evolved various strategies to counteract the production and action of type I interferons, which mobilize the front-line defense against viral infection. In this study we demonstrate that SARS coronavirus M protein inhibits gene transcription of type I interferons. M protein potently antagonizes the activation of interferon-stimulated response element-dependent transcription by double-stranded RNA, RIG-I, MDA5, TBK1, IKKϵ, and virus-induced signaling adaptor (VISA) but has no influence on the transcriptional activity of this element when IRF3 or IRF7 is overexpressed. M protein physically associates with RIG-I, TBK1, IKKϵ, and TRAF3 and likely sequesters some of them in membrane-associated cytoplasmic compartments. Consequently, the expression of M protein prevents the formation of TRAF3·TANK·TBK1/IKKϵ complex and thereby inhibits TBK1/IKKϵ-dependent activation of IRF3/IRF7 transcription factors. Taken together, our findings reveal a new mechanism by which SARS coronavirus circumvents the production of type I interferons.

scholarly journals CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity

Infection ◽  
2021 ◽  
Author(s):  
Jan-Moritz Doehn ◽  
Christoph Tabeling ◽  
Robert Biesen ◽  
Jacopo Saccomanno ◽  
Elena Madlung ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Disease Severity ◽  
Clinical Studies ◽  
Viral Infections ◽  
Severe Disease ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Signaling ◽  
Expression Levels

AbstractCoronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.

scholarly journals The Membrane Protein of Severe Acute Respiratory Syndrome Coronavirus Functions as a Novel Cytosolic Pathogen-Associated Molecular Pattern To Promote Beta Interferon Induction via a Toll-Like-Receptor-Related TRAF3-Independent Mechanism

mBio ◽  
2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi Wang ◽  
Li Liu
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Driving Force ◽  
M Protein ◽  
Signaling Cascade ◽  
Type I ◽  
Toll Like Receptor ◽  
Beta Interferon ◽  
Molecular Pattern ◽  
Pathogen Associated Molecular Pattern ◽  
First Time

ABSTRACT Most of the intracellular pattern recognition receptors (PRRs) reside in either the endolysosome or the cytoplasm to sense pathogen-derived RNAs, DNAs, or synthetic analogs of double-stranded RNA (dsRNA), such as poly(I:C). However, it remains elusive whether or not a pathogen-derived protein can function as a cytosolic pathogen-associated molecular pattern (PAMP). In this study, we demonstrate that delivering the membrane gene of severe acute respiratory syndrome coronavirus (SARS-CoV) into HEK293T, HEK293ET, and immobilized murine bone marrow-derived macrophage (J2-Mφ) cells significantly upregulates beta interferon (IFN-β) production. Both NF-κB and TBK1-IRF3 signaling cascades are activated by M gene products. M protein rather than M mRNA is responsible for M-mediated IFN-β induction that is preferentially associated with the activation of the Toll-like receptor (TLR) adaptor proteins MyD88, TIRAP, and TICAM2 but not the RIG-I signaling cascade. Blocking the secretion of M protein by brefeldin A (BFA) failed to reverse the M-mediated IFN-β induction. The antagonist of both TLR2 and TLR4 did not impede M-mediated IFN-β induction, indicating that the driving force for the activation of IFN-β production was generated from inside the cells. Inhibition of TRAF3 expression by specific small interfering RNA (siRNA) did not prevent M-mediated IFN-β induction. SARS-CoV pseudovirus could induce IFN-β production in an M rather than M(V68A) dependent manner, since the valine-to-alanine alteration at residue 68 in M protein markedly inhibited IFN-β production. Overall, our study indicates for the first time that a pathogen-derived protein is able to function as a cytosolic PAMP to stimulate type I interferon production by activating a noncanonical TLR signaling cascade in a TRAF3-independent manner. IMPORTANCE Viral protein can serve as a pathogen-associated molecular pattern (PAMP) that is usually recognized by certain pathogen recognition receptors (PRRs) on the cell surface, such as Toll-like receptor 2 (TLR2) and TLR4. In this study, we demonstrate that the membrane (M) protein of SARS-CoV can directly promote the activation of both beta interferon (IFN-β) and NF-κB through a TLR-related signaling pathway independent of TRAF3. The driving force for M-mediated IFN-β production is most likely generated from inside the cells. M-mediated IFN-β induction was confirmed at the viral infection level since a point mutation at the V68 residue of M markedly inhibited SARS-CoV pseudovirally induced IFN-β production. Thus, the results indicate for the first time that SARS-CoV M protein may function as a cytosolic PAMP to stimulate IFN-β production by activating a TLR-related TRAF3-independent signaling cascade.

scholarly journals Raftlin Is Involved in the Nucleocapture Complex to Induce Poly(I:C)-mediated TLR3 Activation

2011 ◽  
Vol 286 (12) ◽  
pp. 10702-10711 ◽  
Author(s):  
Ayako Watanabe ◽  
Megumi Tatematsu ◽  
Kazuko Saeki ◽  
Sachiko Shibata ◽  
Hiroaki Shime ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Cell Entry ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Myeloid Dendritic Cells ◽  
Double Stranded Rna ◽  
Cytoplasmic Rna ◽  
Mediate Cell ◽  
Tlr3 Activation

The double-stranded RNA analog, poly(I:C), extracellularly activates both the endosomal Toll-like receptor (TLR) 3 and the cytoplasmic RNA helicase, melanoma differentiation-associated gene 5, leading to the production of type I interferons (IFNs) and inflammatory cytokines. The mechanism by which extracellular poly(I:C) is delivered to TLR3-positive organelles and the cytoplasm remains to be elucidated. Here, we show that the cytoplasmic lipid raft protein, Raftlin, is essential for poly(I:C) cellular uptake in human myeloid dendritic cells and epithelial cells. When Raftlin was silenced, poly(I:C) failed to enter cells and induction of IFN-β production was inhibited. In addition, cellular uptake of B-type oligodeoxynucleotide that shares its uptake receptor with poly(I:C) was suppressed in Raftlin knockdown cells. Upon poly(I:C) stimulation, Raftlin was translocated from the cytoplasm to the plasma membrane where it colocalized with poly(I:C), and thereafter moved to TLR3-positive endosomes. Thus, Raftlin cooperates with the uptake receptor to mediate cell entry of poly(I:C), which is critical for activation of TLR3.

scholarly journals Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) protein inhibits type I and III interferon production by targeting RIG-I/MDA-5 signaling

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Yi Zheng ◽  
Meng-Wei Zhuang ◽  
Lulu Han ◽  
Jing Zhang ◽  
Mei-Ling Nan ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Nuclear Translocation ◽  
Ectopic Expression ◽  
Antiviral Immunity ◽  
Typical Feature ◽  
M Protein ◽  
Poly I:C ◽  
Type I ◽  
Vesicular Stomatitis ◽  
Insight Into

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread worldwide and has affected more than 10 million individuals. A typical feature of COVID-19 is the suppression of type I and III interferon (IFN)-mediated antiviral immunity. However, the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive. Here, we reported that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling. In addition, the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1, thus preventing the formation of the multiprotein complex containing RIG-I, MAVS, TRAF3, and TBK1 and subsequently impeding the phosphorylation, nuclear translocation, and activation of IRF3. Consequently, ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus. Taken together, these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.

scholarly journals Roles of Toll-Like Receptor 3 in Human Tumors

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Zheng ◽  
Song Li ◽  
Hui Yang
Keyword(s):  
Cell Lines ◽  
Human Tumors ◽  
Type I Interferons ◽  
Type I ◽  
Toll Like Receptor ◽  
Double Stranded Rna ◽  
Important Group ◽  
Important Member ◽  
Different Types ◽  
Molecular Patterns

Toll-like receptor 3 (TLR3) is an important member of the TLR family, which is an important group of pathogen-associated molecular patterns. TLR3 can recognize double-stranded RNA and induce activation of NF-κB and the production of type I interferons. In addition to its immune-associated role, TLR3 has also been detected in some tumors. However TLR3 can play protumor or antitumor roles in different tumors or cell lines. Here, we review the basic signaling associated with TLR3 and the pro- or antitumor roles of TLR3 in different types of tumors and discuss the possible reasons for the opposing roles of TLR3 in tumors.

scholarly journals COVID-19: etiology, clinical picture, treatment

2020 ◽  
Vol 10 (3) ◽  
pp. 421-445 ◽  
Author(s):  
M. Yu. Shchelkanov ◽  
L. V. Kolobukhina ◽  
O. A. Burgasova ◽  
I. S. Kruzhkova ◽  
V. V. Maleev
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Clinical Picture ◽  
Influenza A ◽  
Artificial Respiration ◽  
Blood Oxygenation ◽  
Influenza Viruses ◽  
Type I Interferons ◽  
Type I ◽  
Similar System ◽  
History Of

Whereas the XX century marked the history of acute respiratory disease investigation as a period for generating in-depth system of combating influenza viruses (Articulavirales: Orthomyxoviridae, Alpha-/Betainfluenzavirus) (based on environmental and virological monitoring of influenza A virus in its natural reservoir — aquatic and semi-aquatic birds — to supervising epidemic influenza), a similar system is necessary to build up in the XXI century with regard to especially dangerous betacoronaviruses (Nidovirales: Coronaviridae, Betacoronavirus): Severe acute respiratory syndrome-related coronavirus (SARS-CoV) (subgenus Sarbecovirus), Severe acute respiratory syndrome-related coronavirus 2 (SARSCoV-2) (Sarbecovirus), Middle East respiratory syndrome-related coronavirus (MERS-CoV) (Merbecovirus). This became particularly evident after pandemic potential has been revealed in 2020 by the SARS-CoV-2. This review provides an insight into the historic timeline of discovering this virus, its current taxonomy, ecology, virion morphology, life cycle, molecular biology, pathogenesis and clinical picture of the etiologically related COVID-19 (Coronavirus disease 2019) as well as data available in the scientific literature on the anti-SARS-CoV-2-effectiveness of passive immunotherapy and most debated drugs used to treat COVID-19: Chloroquine, Hydroxychloroquine, Nitazoxanide, Ivermectin, Lopinavir and Ritonavir, Camostat mesilate, Remdesivir, Ribavirin, Tocilizumab, Anakinra, corticosteroids, and type I interferons. The pathogenesis of SARS-CoV-2 infection implicates decreased efficacy of artificial respiration, which, in this case might be replaced by more efficient extracorporeal membrane blood oxygenation supplemented with nitrogen oxide and/or Heliox inhalations.

scholarly journals KAT8 selectively inhibits antiviral immunity by acetylating IRF3

2019 ◽  
Vol 216 (4) ◽  
pp. 772-785 ◽  
Author(s):  
Wanwan Huai ◽  
Xingguang Liu ◽  
Chunmei Wang ◽  
Yunkai Zhang ◽  
Xi Chen ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Transcriptional Activity ◽  
Critical Role ◽  
Type I Interferons ◽  
Type I ◽  
Gene Promoters ◽  
Innate Immune Responses ◽  
Antiviral Immune Response ◽  
Lysine Acetyltransferase ◽  
Antiviral Innate Immunity

The transcription factor interferon regulatory factor 3 (IRF3) is essential for virus infection–triggered induction of type I interferons (IFN-I) and innate immune responses. IRF3 activity is tightly regulated by conventional posttranslational modifications (PTMs) such as phosphorylation and ubiquitination. Here, we identify an unconventional PTM of IRF3 that directly inhibits its transcriptional activity and attenuates antiviral immune response. We performed an RNA interference screen and found that lysine acetyltransferase 8 (KAT8), which is ubiquitously expressed in immune cells (particularly in macrophages), selectively inhibits RNA and DNA virus–triggered IFN-I production in macrophages and dendritic cells. KAT8 deficiency protects mice from viral challenge by enhancing IFN-I production. Mechanistically, KAT8 directly interacts with IRF3 and mediates IRF3 acetylation at lysine 359 via its MYST domain. KAT8 inhibits IRF3 recruitment to IFN-I gene promoters and decreases the transcriptional activity of IRF3. Our study reveals a critical role for KAT8 and IRF3 lysine acetylation in the suppression of antiviral innate immunity.

scholarly journals Interferon priming enables cells to partially overturn the SARS coronavirus-induced block in innate immune activation

2009 ◽  
Vol 90 (11) ◽  
pp. 2686-2694 ◽  
Author(s):  
Thomas Kuri ◽  
Xiaonan Zhang ◽  
Matthias Habjan ◽  
Luis Martínez-Sobrido ◽  
Adolfo García-Sastre ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Major Effect ◽  
Plasmacytoid Dendritic Cells ◽  
Effector Proteins ◽  
Innate Immune ◽  
Type I Interferons ◽  
Individual Treatment ◽  
Type I ◽  
Sars Coronavirus ◽  
Cytokines And Chemokines

SARS coronavirus (SARS-CoV) is known to efficiently suppress the induction of antiviral type I interferons (IFN-α/β) in non-lymphatic cells through inhibition of the transcription factor IRF-3. Plasmacytoid dendritic cells, in contrast, respond to infection with production of high levels of IFNs. Here, we show that pretreatment of non-lymphatic cells with small amounts of IFN-α (IFN priming) partially overturns the block in IFN induction imposed by SARS-CoV. IFN priming combined with SARS-CoV infection substantially induced genes for IFN induction, IFN signalling, antiviral effector proteins, ubiquitination and ISGylation, antigen presentation and other cytokines and chemokines, whereas each individual treatment had no major effect. Curiously, however, despite this typical IFN response, neither IRF-3 nor IRF-7 was transported to the nucleus as a sign of activation. Taken together, our results suggest that (i) IFN, as it is produced by plasmacytoid dendritic cells, could enable tissue cells to launch a host response to SARS-CoV, (ii) IRF-3 and IRF-7 may be active at subdetectable levels, and (iii) SARS-CoV does not activate IRF-7.

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