scholarly journals Mechanism of Rhinovirus Immunity and Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Zuqin Yang ◽  
Hannah Mitländer ◽  
Tytti Vuorinen ◽  
Susetta Finotto
Keyword(s):  
Viral Replication ◽  
Defense Mechanisms ◽  
Rna Virus ◽  
Antiviral Agents ◽  
Mucosal Barrier ◽  
Type I ◽  
Viral Spread ◽  
Immunosuppressive Cytokine ◽  
Infected Cells ◽  
Viral Components

The majority of asthma exacerbations in children are caused by Rhinovirus (RV), a positive sense single stranded RNA virus of the Picornavirus family. The host has developed virus defense mechanisms that are mediated by the upregulation of interferon-activated signaling. However, the virus evades the immune system by inducing immunosuppressive cytokines and surface molecules like programmed cell death protein 1 (PD-1) and its ligand (PD-L1) on immunocompetent cells. Initially, RV infects epithelial cells, which constitute a physiologic mucosal barrier. Upon virus entrance, the host cell immediately recognizes viral components like dsRNA, ssRNA, viral glycoproteins or CpG-DNA by host pattern recognition receptors (PRRs). Activation of toll like receptors (TLR) 3, 7 and 8 within the endosome and through MDA-5 and RIG-I in the cytosol leads to the production of interferon (IFN) type I and other antiviral agents. Every cell type expresses IFNAR1/IFNAR2 receptors thus allowing a generalized antiviral activity of IFN type I resulting in the inhibition of viral replication in infected cells and preventing viral spread to non-infected cells. Among immune evasion mechanisms of the virus, there is downregulation of IFN type I and its receptor as well as induction of the immunosuppressive cytokine TGF-β. TGF-β promotes viral replication and is associated with induction of the immunosuppression signature markers LAP3, IDO and PD-L1. This article reviews the recent advances on the regulation of interferon type I expression in association with RV infection in asthmatics and the immunosuppression induced by the virus.

scholarly journals Transcriptional role of p53 in interferon-mediated antiviral immunity

2008 ◽  
Vol 205 (8) ◽  
pp. 1929-1938 ◽  
Author(s):  
César Muñoz-Fontela ◽  
Salvador Macip ◽  
Luis Martínez-Sobrido ◽  
Lauren Brown ◽  
Joseph Ashour ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Viral Replication ◽  
Viral Infections ◽  
Suppressor Gene ◽  
Central Component ◽  
Type I ◽  
Infected Cells

Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424:516–523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene.

scholarly journals RAGE inhibits human respiratory syncytial virus syncytium formation by interfering with F-protein function

2013 ◽  
Vol 94 (8) ◽  
pp. 1691-1700 ◽  
Author(s):  
Jane Tian ◽  
Kelly Huang ◽  
Subramaniam Krishnan ◽  
Catherine Svabek ◽  
Daniel C. Rowe ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Syncytium Formation ◽  
Human Respiratory Syncytial Virus ◽  
Host Cells ◽  
Type I ◽  
F Protein ◽  
Viral Spread ◽  
Infected Cells ◽  
Syncytial Virus

Human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infection. Infection is critically dependent on the RSV fusion (F) protein, which mediates fusion between the viral envelope and airway epithelial cells. The F protein is also expressed on infected cells and is responsible for fusion of infected cells with adjacent cells, resulting in the formation of multinucleate syncytia. The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor that is constitutively highly expressed by type I alveolar epithelial cells. Here, we report that RAGE protected HEK cells from RSV-induced cell death and reduced viral titres in vitro. RAGE appeared to interact directly with the F protein, but, rather than inhibiting RSV entry into host cells, virus replication and budding, membrane-expressed RAGE or soluble RAGE blocked F-protein-mediated syncytium formation and sloughing. These data indicate that RAGE may contribute to protecting the lower airways from RSV by inhibiting the formation of syncytia, viral spread, epithelial damage and airway obstruction.

scholarly journals SARS-CoV-2 infected cells trigger an acute antiviral response mediated by Plasmacytoid dendritic cells in mild but not severe COVID-19 patients

2021 ◽  
Author(s):  
Manon Venet ◽  
Margarida Sa Ribeiro ◽  
Elodie Décembre ◽  
Alicia Bellomo ◽  
Garima Joshi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antiviral Response ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
List Type ◽  
Viral Spread ◽  
Infected Cells ◽  
Specialized Function ◽  
Severity Of The Disease ◽  
Acute Antiviral Response

AbstractType 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.HighlightspDCs are immune cells against SARS-CoV-2-infected cellspDC-mediated IFN-I/λ response against SARS-CoV-2 infected cells control COVID- 19 progressionpDC response by SARS-CoV-2 is restricted to IRF7-prioritized signaling leading to antiviral controlpDC antiviral response directed toward contacting SARS-CoV-2-infected cells

scholarly journals Differential Control of BST2 Restriction and Plasmacytoid Dendritic Cell Antiviral Response by Antagonists Encoded by HIV-1 Group M and O Strains

2016 ◽  
Vol 90 (22) ◽  
pp. 10236-10246 ◽  
Author(s):  
Mariana G. Bego ◽  
Lijun Cong ◽  
Katharina Mack ◽  
Frank Kirchhoff ◽  
Éric A. Cohen
Keyword(s):  
Dendritic Cell ◽  
Mononuclear Cells ◽  
Plasmacytoid Dendritic Cell ◽  
Viral Assembly ◽  
Effective Control ◽  
Type I ◽  
Antiviral Responses ◽  
Viral Spread ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT BST2/tetherin is a type I interferon (IFN-I)-stimulated host factor that restricts the release of HIV-1 by entrapping budding virions at the cell surface. This membrane-associated protein can also engage and activate the plasmacytoid dendritic cell (pDC)-specific immunoglobulin-like transcript 7 (ILT7) inhibitory receptor to downregulate the IFN-I response by pDCs. Pandemic HIV-1 group M uses Vpu (M-Vpu) to counteract the two BST2 isoforms (long and short) that are expressed in human cells. M-Vpu efficiently downregulates surface long BST2, while it displaces short BST2 molecules away from viral assembly sites. We recently found that this attribute is used by M-Vpu to activate the BST2/ILT7-dependent negative-feedback pathway and to suppress pDC IFN-I responses during sensing of infected cells. However, whether this property is conserved in endemic HIV-1 group O, which has evolved Nef (O-Nef) to counteract specifically the long BST2 isoform, remains unknown. In the present study, we validated that O-Nefs have the capacity to downregulate surface BST2 and enhance HIV-1 particle release although less efficiently than M-Vpu. In contrast to M-Vpu, O-Nef did not efficiently enhance viral spread in T cell culture or displace short BST2 from viral assembly sites to prevent its occlusion by tethered HIV-1 particles. Consequently, O-Nef impairs the ability of BST2 to activate negative ILT7 signaling to suppress the IFN-I response by pDC-containing peripheral blood mononuclear cells (PBMCs) during sensing of infected cells. These distinctive features of BST2 counteraction by O-Nefs may in part explain the limited spread of HIV-1 group O in the human population. IMPORTANCE The geographical distributions and prevalences of different HIV-1 groups show large variations. Understanding drivers of distinctive viral spread may aid in the development of therapeutic strategies for controlling the spread of HIV-1 pandemic strains. The differential spread of HIV-1 groups appears to be linked to their capacities to antagonize the long and short isoforms of the BST2 restriction factor. We found that the endemic HIV-1 group O-encoded BST2 antagonist Nef is unable to counteract the restriction mediated by short BST2, a condition that impairs its ability to activate ILT7 and suppress pDC antiviral responses. This is in contrast to the pandemic HIV-1 group M-specified BST2 countermeasure Vpu, which displays a diverse array of mechanisms to counteract short and long BST2 isoforms, an attribute that allows the effective control of pDC antiviral responses. These findings may help explain the limited spread of HIV-1 group O as well as the continued predominance of HIV-1 group M throughout the world.

scholarly journals Inhibition of cytosolic phospholipase A2α impairs an early step of coronavirus replication in cell culture

2017 ◽  
pp. JVI.01463-17 ◽  
Author(s):  
Christin Müller ◽  
Martin Hardt ◽  
Dominik Schwudke ◽  
Benjamin W. Neuman ◽  
Stephan Pleschka ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Lipid Metabolism ◽  
Viral Replication ◽  
Broad Spectrum ◽  
Rna Virus ◽  
Viral Rna ◽  
Cellular Lipid ◽  
Cytosolic Phospholipase ◽  
Infected Cells ◽  
Α Activity

Coronavirus replication is associated with intracellular membrane rearrangements in infected cells, resulting in the formation of double membrane vesicles (DMV) and other membranous structures that are referred to as replicative organelles (RO). The latter provide a structural scaffold for viral replication/transcription complexes (RTC) and help to sequester RTC components from recognition by cellular factors involved in antiviral host responses. There is increasing evidence that plus-strand (+) RNA virus replication, including RO formation and virion morphogenesis, affects cellular lipid metabolism and critically depends on enzymes involved in lipid synthesis and processing. Here, we investigated the role of cytosolic phospholipase A2α (cPLA2α) in coronavirus replication using a small-molecular-weight non-peptidic inhibitor (Py-2). Inhibition of cPLA2α activity, which produces lysophospholipids (LPL) by cleaving at thesn-2 position of phospholipids, had profound effects on viral RNA and protein accumulation in human coronavirus 229E-infected Huh-7 cells. Transmission electron microscopy revealed that DMV formation in infected cells was significantly reduced in the presence of the inhibitor. Furthermore, we found that (i) viral RTCs colocalized with LPL-containing membranes, (ii) cellular LPL concentrations were increased in coronavirus-infected cells and (iii) this increase was diminished in the presence of cPLA2α inhibitor Py-2. Py-2 also displayed antiviral activities against other viruses representing theCoronaviridaeandTogaviridaefamilies, while members of thePicornaviridaewere not affected. Taken together, the study provides evidence that cPLA2α activity is critically involved in the replication of various +RNA virus families and may thus represent a candidate target for broad-spectrum antiviral drug development.ImportanceExamples of highly conserved RNA virus proteins that qualify as drug targets for broad-spectrum antivirals remain scarce, resulting in increased efforts to identify and specifically inhibit cellular functions that are essential for the replication of RNA viruses belonging to different genera and families. The present study supports and extends previous conclusions that enzymes involved in cellular lipid metabolism may be tractable targets for broad-spectrum antivirals. We obtained evidence to show that a cellular phospholipase, cPLA2α, which releases fatty acid from thesn-2 position of membrane-associated glycerophospholipids, is critically involved in coronavirus replication, most likely by producing lysophospholipids that are required to form the specialized membrane compartments at which viral RNA synthesis takes place. The importance of this enzyme in coronavirus replication and DMV formation is supported by several lines of evidence, including confocal and electron microscopy, viral replication and lipidomics studies of coronavirus-infected cells treated with a highly specific cPLA2α inhibitor.

scholarly journals Mathematical Modeling of RNA Virus Sensing Pathways Reveals Paracrine Signaling as the Primary Factor Regulating Excessive Cytokine Production

Processes ◽  
2020 ◽  
Vol 8 (6) ◽  
pp. 719 ◽  
Author(s):  
Jordan J. A. Weaver ◽  
Jason E. Shoemaker
Keyword(s):  
Viral Replication ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Rna Viruses ◽  
Rna Virus ◽  
Influenza Infection ◽  
Cytokine Signaling ◽  
Paracrine Signaling ◽  
Interferon Stimulated Genes ◽  
Infected Cells

RNA viruses, such as influenza and Severe Acute Respiratory Syndrome (SARS), invoke excessive immune responses; however, the kinetics that regulate inflammatory responses within infected cells remain unresolved. Here, we develop a mathematical model of the RNA virus sensing pathways, to determine the intracellular events that primarily regulate interferon, an important protein for the activation and management of inflammation. Within the ordinary differential equation (ODE) model, we incorporate viral replication, cell death, interferon stimulated genes’ antagonistic effects on viral replication, and virus sensor protein (TLR and RIG-I) kinetics. The model is parameterized to influenza infection data using Markov chain Monte Carlo and then validated against infection data from an NS1 knockout strain of influenza, demonstrating that RIG-I antagonism significantly alters cytokine signaling trajectory. Global sensitivity analysis suggests that paracrine signaling is responsible for the majority of cytokine production, suggesting that rapid cytokine production may be best managed by influencing extracellular cytokine levels. As most of the model kinetics are host cell specific and not virus specific, the model presented provides an important step to modeling the intracellular immune dynamics of many RNA viruses, including the viruses responsible for SARS, Middle East Respiratory Syndrome (MERS), and Coronavirus Disease (COVID-19).

scholarly journals Inducible MicroRNA-3570 Feedback Inhibits the RIG-I-Dependent Innate Immune Response to Rhabdovirus in Teleost Fish by Targeting MAVS/IPS-1

2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Tianjun Xu ◽  
Qing Chu ◽  
Junxia Cui ◽  
Dekun Bi
Keyword(s):  
Immune Response ◽  
Viral Replication ◽  
Viral Infection ◽  
Rna Virus ◽  
Antiviral Immunity ◽  
Regulation Mechanism ◽  
Type I ◽  
Small Noncoding Rnas ◽  
Immune Balance ◽  
Antiviral Gene

ABSTRACT Effectively recognizing invading viruses and subsequently inducing innate antiviral immunity are essential for host antiviral defense. Although these processes are closely regulated by the host to maintain immune balance, viruses have evolved the ability to downregulate or upregulate these processes for their survival. MicroRNAs (miRNAs) are a family of small noncoding RNAs that play vital roles in modulating host immune response. Accumulating evidence demonstrates that host miRNAs as mediators are involved in regulating viral replication and host antiviral immunity in mammals. However, the underlying regulatory mechanisms in fish species are still poorly understood. Here, we found that rhabdovirus infection significantly upregulated host miR-3570 expression in miiuy croaker macrophages. Induced miR-3570 negatively modulated RNA virus-triggered type I interferon (IFN) and antiviral gene production, thus facilitating viral replication. Furthermore, miR-3570 was found to target and posttranscriptionally downregulate mitochondrial antiviral signaling protein (MAVS), which functions as a platform for innate antiviral signal transduction. Moreover, we demonstrated that miR-3570 suppressed the expression of MAVS, thereby inhibiting MAVS-mediated NF-κB and IRF3 signaling. The collective results demonstrated a novel regulation mechanism of MAVS-mediated immunity during RNA viral infection by miRNA. IMPORTANCE RNA viral infection could upregulate host miR-3570 expression in miiuy croaker macrophages. Induced miR-3570 negatively modulates RNA virus-triggered type I IFN and antiviral gene production, thus facilitating viral replication. Remarkably, miR-3570 could target and inhibit MAVS expression, which thus modulates MAVS-mediated NF-κB and IRF3 signaling. The collective results of this study suggest a novel regulation mechanism of MAVS-mediated immunity during RNA viral infection by miR-3570. Thus, a novel mechanism for virus evasion in fish is proposed.

scholarly journals Rotavirus Antagonizes Cellular Antiviral Responses by Inhibiting the Nuclear Accumulation of STAT1, STAT2, and NF-κB

2009 ◽  
Vol 83 (10) ◽  
pp. 4942-4951 ◽  
Author(s):  
Gavan Holloway ◽  
Thanhmai T. Truong ◽  
Barbara S. Coulson
Keyword(s):  
Gene Expression ◽  
Viral Infection ◽  
Rna Virus ◽  
Host Responses ◽  
Nuclear Accumulation ◽  
Type I ◽  
Nonstructural Proteins ◽  
Necrosis Factor Alpha ◽  
Intracellular Expression ◽  
Infected Cells

ABSTRACT A vital arm of the innate immune response to viral infection is the induction and subsequent antiviral effects of interferon (IFN). Rotavirus reduces type I IFN induction in infected cells by the degradation of IFN regulatory factors. Here, we show that the monkey rotavirus RRV and human rotavirus Wa also block gene expression induced by type I and II IFNs through a mechanism allowing signal transducer and activator of transcription 1 (STAT1) and STAT2 activation but preventing their nuclear accumulation. In infected cells, this may allow rotavirus to block the antiviral actions of IFN produced early in infection or by activated immune cells. As the intracellular expression of rotavirus nonstructural proteins NSP1, NSP3, and NSP4 individually did not inhibit IFN-stimulated gene expression, their involvement in this process is unlikely. RRV and Wa rotaviruses also prevented the tumor necrosis factor alpha-stimulated nuclear accumulation of NF-κB and NF-κB-driven gene expression. In addition, NF-κB was activated by rotavirus infection, confirming earlier findings by others. As NF-κB is important for the induction of IFN and other cytokines during viral infection, this suggests that rotavirus prevents cellular transcription as a means to evade host responses. To our knowledge, this is the first report of the use of this strategy by a double-stranded RNA virus.

scholarly journals Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Brian Webster ◽  
Scott W Werneke ◽  
Biljana Zafirova ◽  
Sébastien This ◽  
Séverin Coléon ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cell ◽  
Rna Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Virus Infections ◽  
Antiviral Responses ◽  
Infected Cells ◽  
Interferon Responses

Type I interferon (IFN-I) responses are critical for the control of RNA virus infections, however, many viruses, including Dengue (DENV) and Chikungunya (CHIKV) virus, do not directly activate plasmacytoid dendritic cells (pDCs), robust IFN-I producing cells. Herein, we demonstrated that DENV and CHIKV infected cells are sensed by pDCs, indirectly, resulting in selective IRF7 activation and IFN-I production, in the absence of other inflammatory cytokine responses. To elucidate pDC immunomodulatory functions, we developed a mouse model in which IRF7 signaling is restricted to pDC. Despite undetectable levels of IFN-I protein, pDC-restricted IRF7 signaling controlled both viruses and was sufficient to protect mice from lethal CHIKV infection. Early pDC IRF7-signaling resulted in amplification of downstream antiviral responses, including an accelerated natural killer (NK) cell-mediated type II IFN response. These studies revealed the dominant, yet indirect role of pDC IRF7-signaling in directing both type I and II IFN responses during arbovirus infections.

scholarly journals Evidence That the Adenovirus Single-Stranded DNA Binding Protein Mediates the Assembly of Biomolecular Condensates to Form Viral Replication Compartments

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1778
Author(s):  
Paloma Hidalgo ◽  
Arturo Pimentel ◽  
Diana Mojica-Santamaría ◽  
Konstantin von Stromberg ◽  
Helga Hofmann-Sieber ◽  
...  
Keyword(s):  
Viral Replication ◽  
Defense Mechanisms ◽  
Binding Protein ◽  
Human Adenovirus ◽  
Time Lapse ◽  
Low Complexity ◽  
Ssdna Binding ◽  
Intrinsically Disordered ◽  
Ssdna Binding Protein ◽  
Infected Cells

A common viral replication strategy is characterized by the assembly of intracellular compartments that concentrate factors needed for viral replication and simultaneously conceal the viral genome from host-defense mechanisms. Recently, various membrane-less virus-induced compartments and cellular organelles have been shown to represent biomolecular condensates (BMCs) that assemble through liquid-liquid phase separation (LLPS). In the present work, we analyze biophysical properties of intranuclear replication compartments (RCs) induced during human adenovirus (HAdV) infection. The viral ssDNA-binding protein (DBP) is a major component of RCs that contains intrinsically disordered and low complexity proline-rich regions, features shared with proteins that drive phase transitions. Using fluorescence recovery after photobleaching (FRAP) and time-lapse studies in living HAdV-infected cells, we show that DBP-positive RCs display properties of liquid BMCs, which can fuse and divide, and eventually form an intranuclear mesh with less fluid-like features. Moreover, the transient expression of DBP recapitulates the assembly and liquid-like properties of RCs in HAdV-infected cells. These results are of relevance as they indicate that DBP may be a scaffold protein for the assembly of HAdV-RCs and should contribute to future studies on the role of BMCs in virus-host cell interactions.

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