scholarly journals Respiratory Syncytial Virus-Mediated NF-κB p65 Phosphorylation at Serine 536 Is Dependent on RIG-I, TRAF6, and IKKβ

2010 ◽  
Vol 84 (14) ◽  
pp. 7267-7277 ◽  
Author(s):  
Fabrice Yoboua ◽  
Alexis Martel ◽  
Annick Duval ◽  
Espérance Mukawera ◽  
Nathalie Grandvaux
Keyword(s):  
Respiratory Syncytial Virus ◽  
Critical Role ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Proinflammatory Response ◽  
Cytokines And Chemokines ◽  
Upstream Regulator ◽  
Rsv Infection ◽  
Oxidase Enzyme ◽  
Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is the etiological agent of acute respiratory diseases, such as bronchiolitis and pneumonia. The exacerbated production of proinflammatory cytokines and chemokines in the airways in response to RSV is an important pillar in the development of these pathologies. As such, a keen understanding of the mechanisms that modulate the inflammatory response during RSV infection is of pivotal importance to developing effective treatment. The NF-κB transcription factor is a major regulator of proinflammatory cytokine and chemokine genes. However, RSV-mediated activation of NF-κB is far from characterized. We recently demonstrated that aside from the well-characterized IκBα phosphorylation and degradation, the phosphorylation of p65 at Ser536 is an essential event regulating the RSV-mediated NF-κB-dependent promoter transactivation. In the present study, using small interfering RNA and pharmacological inhibitors, we now demonstrate that RSV sensing by the RIG-I cytoplasmic receptor triggers a signaling cascade involving the MAVS and TRAF6 adaptors that ultimately leads to p65ser536 phosphorylation by the IKKβ kinase. In a previous study, we highlighted a critical role of the NOX2-containing NADPH oxidase enzyme as an upstream regulator of both the IκBαSer32 and p65Ser536 in human airway epithelial cells. Here, we demonstrate that inhibition of NOX2 significantly decreases IKKβ activation. Taken together, our data identify a new RIG-I/MAVS/TRAF6/IKKβ/p65Ser536 pathway placed under the control of NOX2, thus characterizing a novel regulatory pathway involved in NF-κB-driven proinflammatory response in the context of RSV infection.

scholarly journals Metabolic Reprogramming of Nasal Airway Epithelial Cells Following Infant Respiratory Syncytial Virus Infection

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2055
Author(s):  
Andrew R. Connelly ◽  
Brian M. Jeong ◽  
Mackenzie E. Coden ◽  
Jacob Y. Cao ◽  
Tatiana Chirkova ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Early Life ◽  
Airway Epithelial Cells ◽  
Metabolic Reprogramming ◽  
Flux Analysis ◽  
Nasal Airway ◽  
Airway Epithelial ◽  
Rsv Infection ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is a seasonal mucosal pathogen that infects the ciliated respiratory epithelium and results in the most severe morbidity in the first six months of life. RSV is a common cause of acute respiratory infection during infancy and is an important early-life risk factor strongly associated with asthma development. While this association has been repeatedly demonstrated, limited progress has been made on the mechanistic understanding in humans of the contribution of infant RSV infection to airway epithelial dysfunction. An active infection of epithelial cells with RSV in vitro results in heightened central metabolism and overall hypermetabolic state; however, little is known about whether natural infection with RSV in vivo results in lasting metabolic reprogramming of the airway epithelium in infancy. To address this gap, we performed functional metabolomics, 13C glucose metabolic flux analysis, and RNA-seq gene expression analysis of nasal airway epithelial cells (NAECs) sampled from infants between 2–3 years of age, with RSV infection or not during the first year of life. We found that RSV infection in infancy was associated with lasting epithelial metabolic reprogramming, which was characterized by (1) significant increase in glucose uptake and differential utilization of glucose by epithelium; (2) altered preferences for metabolism of several carbon and energy sources; and (3) significant sexual dimorphism in metabolic parameters, with RSV-induced metabolic changes most pronounced in male epithelium. In summary, our study supports the proposed phenomenon of metabolic reprogramming of epithelial cells associated with RSV infection in infancy and opens exciting new venues for pursuing mechanisms of RSV-induced epithelial barrier dysfunction in early life.

scholarly journals Fosfomycin Suppresses Chemokine Induction in Airway Epithelial Cells Infected with Respiratory Syncytial Virus

2009 ◽  
Vol 16 (6) ◽  
pp. 859-865 ◽  
Author(s):  
Tamaki Okabayashi ◽  
Shin-ichi Yokota ◽  
Yuko Yoto ◽  
Hiroyuki Tsutsumi ◽  
Nobuhiro Fujii
Keyword(s):  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Infectious Diseases ◽  
Airway Epithelial Cells ◽  
Luciferase Reporter ◽  
Airway Epithelial ◽  
Gene Assay ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Rantes Promoter

ABSTRACT Respiratory syncytial virus (RSV) infects airway epithelial cells, causing bronchiolitis and pneumonia. Inflammation is mediated by various cytokines secreted from RSV-infected airway epithelial cells, and it promotes the pathogenesis of RSV-related diseases. Fosfomycin (FOF) is approved as a treatment for various bacterial infectious diseases, including respiratory infectious diseases, in Japan. FOF is suggested to exhibit immunomodulatory effects on lipopolysaccharide-stimulated monocytes and T lymphocytes, in addition to its antimicrobial activity. We investigated the effect of FOF on the cytokine production of an airway epithelial cell line, A549, infected with RSV. RSV-induced cytokines, such as regulated on activation, normal T-cell expressed and secreted (RANTES), interleukin-8 (IL-8), and IL-6, in infected A549 cells. We found that FOF decreased the levels of RSV-induced RANTES and IL-8 but not the level of RSV-induced IL-6. The RANTES promoter was activated by RSV infection. Site-directed mutagenesis analysis of the RANTES promoter showed that NF-κB-binding motifs had a critical role in RSV-induced RANTES promoter activity. A luciferase reporter gene assay and a DNA-binding assay indicated that FOF suppressed the NF-κB activity induced by RSV infection. These results demonstrate that FOF treatment suppresses the RSV-induced transcription of the chemokines RANTES and IL-8 in airway epithelial cells.

scholarly journals Airway Epithelial Derived Cytokines and Chemokines and Their Role in the Immune Response to Respiratory Syncytial Virus Infection

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 106 ◽  
Author(s):  
Glaser ◽  
Coulter ◽  
Shields ◽  
Touzelet ◽  
Power ◽  
...  
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Virus Infection ◽  
Respiratory Syncytial Virus Infection ◽  
Immune Cells ◽  
Airway Epithelial ◽  
Antiviral Immune Response ◽  
Cytokines And Chemokines ◽  
Rsv Infection ◽  
Syncytial Virus

The airway epithelium is the primary target of respiratory syncytial virus infection. It is an important component of the antiviral immune response. It contributes to the recruitment and activation of innate immune cells from the periphery through the secretion of cytokines and chemokines. This paper provides a broad review of the cytokines and chemokines secreted from human airway epithelial cell models during respiratory syncytial virus (RSV) infection based on a comprehensive literature review. Epithelium-derived chemokines constitute most inflammatory mediators secreted from the epithelium during RSV infection. This suggests chemo-attraction of peripheral immune cells, such as monocytes, neutrophils, eosinophils, and natural killer cells as a key function of the epithelium. The reports of epithelium-derived cytokines are limited. Recent research has started to identify novel cytokines, the functions of which remain largely unknown in the wider context of the RSV immune response. It is argued that the correct choice of in vitro models used for investigations of epithelial immune functions during RSV infection could facilitate greater progress in this field.

scholarly journals Respiratory syncytial virus activates Rab5a to suppress IRF1-dependent IFN-λ production, subverting the antiviral defense of airway epithelial cells

2021 ◽  
Author(s):  
Shi Mo ◽  
Wei Tang ◽  
Jun Xie ◽  
Sisi Chen ◽  
Luo Ren ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Antiviral Immunity ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Novel Therapeutics ◽  
Potential Target ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Respiratory Epithelial

The limited antiviral options and lack of an effective vaccine against human respiratory syncytial virus (RSV) highlight the need for a novel antiviral therapy. One alternative is to identify and target the host factors required for viral infection. Here, using RNA interference to knock down Rab proteins, we provide multiple lines of evidence that Rab5a is required for RSV infection: (a) Rab5a is upregulated both in RSV-A2-infected A549 cells and RSV-A2-challenged BALB/c mice’s airway epithelial cells at early infection phase; (b) shRNA-mediated knockdown of Rab5a is associated with reduced lung pathology in RSV A2 challenged mice; (c) Rab5a expression is correlated with disease severity of RSV infection of infants. Knockdown of Rab5a increases IFN-λ (lambda) production by mediating IRF1 nuclear translocation. Our results highlight a new role for Rab5a in RSV infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity, which suggests that Rab5a is a potential target for novel therapeutics against RSV infection. Importance This study highlights the important role of Rab5a in RSV infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity and attenuates inflammation of the airway, which suggests that Rab5a is a powerful potential target for novel therapeutics against RSV infection.

scholarly journals Incomplete Regulation of NF-κB by IκBα during Respiratory Syncytial Virus Infection in A549 Cells

1999 ◽  
Vol 73 (5) ◽  
pp. 4502-4507 ◽  
Author(s):  
Michael A. Fiedler ◽  
Kara Wernke-Dollries
Keyword(s):  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
A549 Cells ◽  
Inhibitory Effect ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) infection of airway epithelial cells results in persistent NF-κB activation and NF-κB-mediated interleukin-8 production. Previous studies in airway epithelial cells demonstrated that tumor necrosis factor alpha (TNF-α)-induced NF-κB activation is transient due to regulation by IκBα. However, during RSV infection, IκBα has only a partial inhibitory effect on NF-κB activation. Studies presented here demonstrate that neither increased IκBα production which occurs as a result of RSV-induced NF-κB activation nor inhibition of proteasome-mediated IκBα degradation results in a reversal of RSV-induced NF-κB activation. Thus, while manipulation of IκBα results in reversal of TNF-α-induced NF-κB activation, manipulation of IκBα does not result in a reversal of RSV-induced NF-κB activation.

scholarly journals Retinoic Acid-Inducible Gene I Mediates Early Antiviral Response and Toll-Like Receptor 3 Expression in Respiratory Syncytial Virus-Infected Airway Epithelial Cells

2006 ◽  
Vol 81 (3) ◽  
pp. 1401-1411 ◽  
Author(s):  
Ping Liu ◽  
Mohammad Jamaluddin ◽  
Kui Li ◽  
Roberto P. Garofalo ◽  
Antonella Casola ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Toll Like Receptor ◽  
Isg15 Expression ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Inducible Gene

ABSTRACT Respiratory syncytial virus (RSV) is one of the most common viral pathogens causing severe lower respiratory tract infections in infants and young children. Infected host cells detect and respond to RNA viruses using different mechanisms in a cell-type-specific manner, including retinoic acid-inducible gene I (RIG-I)-dependent and Toll-like receptor (TLR)-dependent pathways. Because the relative contributions of these two pathways in the recognition of RSV infection are unknown, we examined their roles in this study. We found that RIG-I helicase binds RSV transcripts within 12 h of infection. Short interfering RNA (siRNA)-mediated RIG-I “knockdown” significantly inhibited early nuclear factor-κB (NF-κB) and interferon response factor 3 (IRF3) activation 9 h postinfection (p.i.). Consistent with this finding, RSV-induced beta interferon (IFN-β), interferon-inducible protein 10 (IP-10), chemokine ligand 5 (CCL-5), and IFN-stimulated gene 15 (ISG15) expression levels were decreased in RIG-I-silenced cells during the early phase of infection but not at later times (18 h p.i.). In contrast, siRNA-mediated TLR3 knockdown did not affect RSV-induced NF-κB binding but did inhibit IFN-β, IP-10, CCL-5, and ISG15 expression at late times of infection. Further studies revealed that TLR3 knockdown significantly reduced NF-κB/RelA transcription by its ability to block the activating phosphorylation of NF-κB/RelA at serine residue 276. We further found that TLR3 induction following RSV infection was regulated by RIG-I-dependent IFN-β secreted from infected airway epithelial cells and was mediated by both IFN response-stimulated element (ISRE) and signal transducer and activator of transcription (STAT) sites in its proximal promoter. Together these findings indicate distinct temporal roles of RIG-I and TLR3 in mediating RSV-induced innate immune responses, which are coupled to distinct pathways controlling NF-κB activation.

scholarly journals Infantile respiratory syncytial virus and human rhinovirus infections: respective role in inception and persistence of wheezing

2014 ◽  
Vol 45 (3) ◽  
pp. 774-789 ◽  
Author(s):  
Giovanni A. Rossi ◽  
Andrew A. Colin
Keyword(s):  
Respiratory Syncytial Virus ◽  
Airway Disease ◽  
Epidemiological Studies ◽  
Human Rhinovirus ◽  
Allergic Sensitisation ◽  
Cytokines And Chemokines ◽  
Rsv Infection ◽  
History Of ◽  
Syncytial Virus

There is evidence that respiratory viruses play a key role in the development and exacerbation of obstructive respiratory diseases in children. This review attempts to juxtapose the separate profiles and prototypes of pathogenenetic mechanisms represented by the two most common amongst such viruses: respiratory syncytial virus (RSV) and human rhinovirus (HRV).RSV represents the most common agent of severe airway disease in infants and young children, and is predominant in winter months. Large epidemiological studies have revealed an unequivocal relationship between RSV infection and subsequent wheezing into childhood, thought to be related to long-term changes in neuroimmune control of the airways rather than allergic sensitisation.HRV is a highly diverse group of viruses that affect subjects of all ages, is ubiquitous and occurs year-round. In contrast to RSV, infections with HRV cause minimal cytotoxicity but induce a rapid production of cytokines and chemokines with amplification of the inflammatory response. The susceptibility to HRV-induced bronchiolitis and subsequent wheezing appears to be linked to individual predisposition since it is often associated with a family or personal history of asthma/atopy.Thus, RSV probably serves as an “inducer” rather than a “trigger”. Conversely, HRVs seem to serve as a “trigger” rather than an “inducer” in predisposed individuals.

scholarly journals Fcγ Receptor IIa (FCGR2A) Polymorphism Is Associated With Severe Respiratory Syncytial Virus Disease in Argentinian Infants

2020 ◽  
Vol 10 ◽  
Author(s):  
María Pía Holgado ◽  
Silvina Raiden ◽  
Inés Sananez ◽  
Vanesa Seery ◽  
Leonardo De Lillo ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Virus Disease ◽  
Severe Disease ◽  
Critical Role ◽  
Fcγ Receptor ◽  
Factors Associated ◽  
Severe Group ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
The Relationship

BackgroundMost patients with respiratory syncytial virus (RSV) infection requiring hospitalization have no risk factors for severe disease. Genetic variation in the receptor for the Fc portion of IgG (FcγR) determines their affinity for IgG subclasses driving innate and adaptive antiviral immunity. We investigated the relationship between FcγRIIa-H131R polymorphism and RSV disease.MethodsBlood samples were collected from 182 infants ≤24-month-old (50 uninfected, 114 RSV-infected with moderate course and 18 suffering severe disease). FcγRIIa-H131R SNP genotypic frequencies (HH, HR, RR) and anti-RSV IgG1, IgG2 and IgG3 levels were studied.ResultsGenotypic frequencies for FcγRIIa-H131R SNP were comparable between uninfected and RSV-infected infants. In contrast, we found a significant higher frequency of HH genotype in severe RSV-infected children compared to moderate patients. Among severe group, HH infants presented more factors associated to severity than HR or RR patients did. Furthermore, compared to moderate RSV-infected infants, severe patients showed higher levels of anti-RSV IgG1 and IgG3.ConclusionsWe found an association between an FcγRIIa (H131) polymorphism and severe RSV disease, which points towards a critical role for interactions between FcγRs and immune complexes in RSV pathogenesis. This genetic factor could also predict the worse outcome and identify those infants at risk during hospitalization.

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