scholarly journals IκB Kinase Is a Critical Regulator of Chemokine Expression and Lung Inflammation in Respiratory Syncytial Virus Infection

2004 ◽  
Vol 78 (5) ◽  
pp. 2232-2241 ◽  
Author(s):  
Helene A. Haeberle ◽  
Antonella Casola ◽  
Zoran Gatalica ◽  
Sharon Petronella ◽  
Hans-Juergen Dieterich ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Airway Inflammation ◽  
Critical Role ◽  
Regulatory Protein ◽  
Mucosal Inflammation ◽  
Specific Cell ◽  
Iκb Kinase ◽  
Syncytial Virus ◽  
Tract Infections

ABSTRACT Respiratory syncytial virus (RSV) is the major etiologic agent of severe epidemic lower respiratory tract infections in infancy. Airway mucosal inflammation plays a critical role in the pathogenesis of RSV disease in both natural and experimental infections. RSV is among the most potent biological stimuli that induce the expression of inflammatory genes, including those encoding chemokines, but the mechanism(s) that controls virus-mediated airway inflammation in vivo has not been fully elucidated. Herein we show that the inoculation of BALB/c mice with RSV results in rapid activation of the multisubunit IκB kinase (IKK) in lung tissue. IKK transduces upstream activating signals into the rate-limiting phosphorylation (and proteolytic degradation) of IκBα, the inhibitory subunit that under normal conditions binds to the nuclear factor (NF)-κB complex and keeps it in an inactive cytoplasmic form. Mice treated intranasally with interleukin-10 or with a specific cell-permeable peptide that blocks the association of the catalytic subunit IKKβ with the regulatory protein NEMO showed a striking reduction of lung NF-κB DNA binding activity, chemokine gene expression, and airway inflammation in response to RSV infection. These findings suggest that IKKβ may be a potential target for the treatment of acute or chronic inflammatory diseases of the lung.

scholarly journals Loss of versican and production of hyaluronan in lung epithelial cells are associated with airway inflammation during RSV infection

2020 ◽  
pp. jbc.RA120.016196
Author(s):  
Gerald G. Kellar ◽  
Kaitlyn A. Barrow ◽  
Lucille M. Rich ◽  
Jason S. Debley ◽  
Thomas N. Wight ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Ex Vivo ◽  
Lung Epithelial Cells ◽  
In Vivo Studies ◽  
Critical Feature ◽  
Human Lung Fibroblast ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections

Airway inflammation is a critical feature of lower respiratory tract infections caused by viruses such as respiratory syncytial virus (RSV). A growing body of literature has demonstrated the importance of extracellular matrix (ECM) changes such as the accumulation of hyaluronan (HA) and versican in the subepithelial space in promoting airway inflammation; however, whether these factors contribute to airway inflammation during RSV infection remains unknown. To test the hypothesis that RSV infection promotes inflammation via altered HA and versican production, we studied an ex vivo human bronchial epithelial cell (BEC)/human lung fibroblast (HLF) co-culture model. RSV infection of BEC/HLF co-cultures led to decreased hyaluronidase expression by HLFs, increased accumulation of HA, and enhanced adhesion of U937 cells as would be expected with increased HA. HLF production of versican was not altered following RSV infection; however, BEC production of versican was significantly downregulated following RSV infection. In vivo studies with epithelial-specific versican-deficient mice [SPC-Cre(+) Vcan-/-] demonstrated that RSV infection led to increased HA accumulation compared to control mice which also coincided with decreased hyaluronidase expression in the lung. SPC-Cre(+) Vcan-/- mice demonstrated enhanced recruitment of monocytes and neutrophils in bronchoalveolar lavage fluid and increased neutrophils in the lung compared to SPC-Cre(-) RSV-infected littermates. Taken together, these data demonstrate that altered ECM accumulation of HA occurs following RSV infection and may contribute to airway inflammation. Additionally, loss of epithelial expression of versican promotes airway inflammation during RSV infection further demonstrating that versican’s role in inflammatory regulation is complex and dependent on the microenvironment.

scholarly journals RFI-641, a Potent Respiratory Syncytial Virus Inhibitor

2002 ◽  
Vol 46 (3) ◽  
pp. 841-847 ◽  
Author(s):  
Clayton C. Huntley ◽  
William J. Weiss ◽  
Anna Gazumyan ◽  
Aron Buklan ◽  
Boris Feld ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Tract Infections ◽  
Syncytium Formation ◽  
Therapeutic Window ◽  
Monkey Model ◽  
Cotton Rats ◽  
Syncytial Virus ◽  
Tract Infections

ABSTRACT Human respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. RFI-641 is a novel anti-RSV agent with potent in vitro and in vivo activity. RFI-641 is active against both RSV type A and B strains. The viral specificity and the large therapeutic window of RFI-641 (>100-fold) indicate that the antiviral activity of the compound is not due to adverse effects on normal cells. The potent in vitro activity of RFI-641 can be translated to efficacy in vivo: RFI-641 is efficacious when administered prophylactically by the intranasal route in mice, cotton rats, and African green monkeys. RFI-641 is also efficacious when administered therapeutically (24 h postinfection) in the monkey model. Mechanism of action studies indicate that RFI-641 blocks viral F protein-mediated fusion and cell syncytium formation.

scholarly journals Protein Kinase R Is a Novel Mediator of CD40 Signaling and Plays a Critical Role in Modulating Immunoglobulin Expression during Respiratory Syncytial Virus Infection

2011 ◽  
Vol 18 (12) ◽  
pp. 2060-2066 ◽  
Author(s):  
Sheetal A. Thakur ◽  
Zachary B. Zalinger ◽  
Teresa R. Johnson ◽  
Farhad Imani
Keyword(s):  
Respiratory Syncytial Virus ◽  
B Cells ◽  
Protein Kinase ◽  
Critical Role ◽  
Vital Role ◽  
Protein Kinase R ◽  
Cd40 Ligation ◽  
Syncytial Virus

ABSTRACTEffective immunoglobulin responses play a vital role in protection against most pathogens. However, the molecular mediators and mechanisms responsible for signaling and selective expression of immunoglobulin types remain to be elucidated. Previous studies in our laboratory have demonstrated that protein kinase R (PKR) plays a crucial role in IgE responses to double-stranded RNA (dsRNA)in vitro. In this study, we show that PKR plays a critical role in IgG expression bothin vivoandin vitro. PKR−/−mice show significantly altered serum IgG levels during respiratory syncytial virus (RSV) infection. IgG2a expression is particularly sensitive to a lack of PKR and is below the detection level in mock- or RSV-infected PKR−/−mice. Interestingly, we show that upon activation by anti-CD40 and gamma interferon (IFN-γ), B cells from PKR−/−mice show diminished major histocompatibility complex class II (MHC II), CD80, and CD86 levels on the cell surface compared to wild-type (WT) mice. Our data also show that PKR is necessary for optimal expression of adhesion molecules, such as CD11a and ICAM-1, that are necessary for homotypic aggregation of B cells. Furthermore, in this report we demonstrate for the first time that upon CD40 ligation, PKR is rapidly phosphorylated and activated, indicating that PKR is an early and novel downstream mediator of CD40 signaling pathways.

scholarly journals The larger attachment glycoprotein of respiratory syncytial virus produced in primary human bronchial epithelial cultures reduces infectivity for cell lines

2021 ◽  
Vol 17 (4) ◽  
pp. e1009469
Author(s):  
Tiffany King ◽  
Asuncion Mejias ◽  
Octavio Ramilo ◽  
Mark E. Peeples
Keyword(s):  
Respiratory Syncytial Virus ◽  
Cell Lines ◽  
Virus Infectivity ◽  
Bronchial Epithelial ◽  
Epithelial Cultures ◽  
Differential Infectivity ◽  
Syncytial Virus ◽  
Immortalized Cell ◽  
Tract Infections

Respiratory syncytial virus (RSV) infects the upper and lower respiratory tracts and can cause lower respiratory tract infections in children and elders. RSV has traditionally been isolated, grown, studied and quantified in immortalized cell lines, most frequently HEp-2 cells. However, in vivo RSV infection is modeled more accurately in primary well differentiated human bronchial epithelial (HBE) cultures where RSV targets the ciliated cells and where the putative RSV receptor differs from the receptor on HEp-2 cells. The RSV attachment (G) glycoprotein in virions produced by HEp-2 cells is a highly glycosylated 95 kDa protein with a 32 kDa peptide core. However, virions produced in HBE cultures, RSV (HBE), contain an even larger, 170 kDa, G protein (LgG). Here we show that LgG is found in virions from both subgroups A and B lab-adapted and clinical isolates. Unexpectedly, RSV (HBE) virions were approximately 100-fold more infectious for HBE cultures than for HEp-2 cells. Surprisingly, the cause of this differential infectivity, was reduced infectivity of RSV (HBE) on HEp-2 cells rather than enhanced infectivity on HBE cultures. The lower infectivity of RSV(HBE) for HEp-2 cells is caused by the reduced ability of LgG to interact with heparan sulfate proteoglycans (HSPG), the RSV receptor on HEp-2 cells. The discovery of different infectivity corresponding with the larger form of the RSV attachment protein when produced by HBE cultures highlights the importance of studying a virus produced by its native host cell and the potential impact on quantifying virus infectivity on cell lines where the virus entry mechanisms differ from their natural target cell.

scholarly journals Development of surface engineered antigenic exosomes as vaccines for respiratory syncytial virus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Suyeon Hong ◽  
Shaobo Ruan ◽  
Zachary Greenberg ◽  
Mei He ◽  
Jodi L. McGill
Keyword(s):  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
Ex Vivo ◽  
Subcutaneous Administration ◽  
Antigenic Peptides ◽  
Vaccine Platform ◽  
Mhc I ◽  
Syncytial Virus ◽  
Tract Infections

AbstractRespiratory syncytial virus (RSV) is one of the main pathogens associated with lower respiratory tract infections in infants and young children worldwide. Exosomes secreted by antigen presenting cells (APCs) can elicit immune responses by carrying major histocompatibility complex (MHC) class I molecules complexed with antigenic peptides and other co-stimulating factors. Therefore, we developed novel immunomagnetic nanographene particles to sequentially isolate, surface engineer, and release intact dendritic cell (DC) exosomes for use as a potential vaccine platform against RSV. The H-2Db-restricted, immunodominant peptides from RSV (M187–195 and NS161–75) were introduced to MHC-I on DC-derived exosomes to express peptide/MHC-I (pMHC-I) complexes. A mouse model of RSV infection was used to define the immunogenicity of surface engineered exosomes for activating virus-specific immune responses. Ex vivo assays demonstrated that engineered exosomes carrying RSV-specific peptides can elicit interferon-gamma (IFN-γ) production by virus-specific CD8+ T cells isolated from RSV-infected C57BL/6 mice. In vivo assays demonstrated that subcutaneous administration of both M187–195 and NS161–75 engineered exosomes to mice, with or without additional adjuvant, appeared safe and well tolerated, however, did not prime antigen-specific CD8+ T cell responses. Surface engineered exosomes are immunogenic and promising for further development as a vaccine platform.

scholarly journals Neuromedin U Induces Pulmonary Group 2 Innate Lymphoid Cell Activation via NMUR1 Pathway During Acute Respiratory Syncytial Virus Infection

2021 ◽  
Author(s):  
Weiwei LIU ◽  
Si Wang ◽  
Jia Wang ◽  
Rui Zheng ◽  
Dalu Wang ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Airway Inflammation ◽  
Cell Activation ◽  
Regulatory Effect ◽  
Key Factor ◽  
Rsv Infection ◽  
Group 2 ◽  
Syncytial Virus ◽  
Underlying Mechanisms

Abstract Background：The activated group 2 innate lymphocytes (ILC2s) play a crucial role in respiratory syncytial virus (RSV)-induced airway inflammation by secreting large amount of type 2 cytokines. Although the classical activator IL-33 is the key factor for ILC2 activation, a regulatory effect of neurotransmitter-neuromedin U (NMU) has also been reported. However, whether and how NMU can be elicited by RSV infection and regulate pulmonary ILC2 activation remains unclear.Methods： The regulatory effect and underlying mechanisms of NMU on ILC2 activation were determined by using RSV-infected wild-type and NMU-knockout mice. The expression of NMU in the lungs and NMUR1 on ILC2s were measured by Real-time PCR and Western blot. Flow cytometry and ELISA were used to detect the proliferation and activation of ILC2s. The type of neurons secreting NMU and its possible secretion mechanism during RSV infection were also analyzed.Results：Acute RSV infection induced the production of NMU in the lungs of mice and up-regulate the expression of NMUR1 on the pulmonary ILC2s. In vivo administration of NMU exacerbated RSV-induced airway inflammation by promoting the proliferation and activation of pulmonary ILC2s via NMUR1 pathway. In this process, PI3K, MEK and NFAT signal proteins might be involved. Furthermore, pulmonary neurons responded to the stimulation of RSV and secreted NMU in TLR4 and TLR7-dependent manners.Conclusion：Our data suggest that NMU is an ILC2 activator other than the classical activator, revealing a novel effect of neurotransmitter on RSV-induced airway inflammation.

scholarly journals Chitinase 3‐like 1 protein plays a critical role in respiratory syncytial virus‐induced airway inflammation

Allergy ◽  
2018 ◽  
Vol 74 (4) ◽  
pp. 685-697 ◽  
Author(s):  
Min Jung Kim ◽  
Doo Hee Shim ◽  
Hye‐Ran Cha ◽  
Kuk‐Young Moon ◽  
Chang Mo Yang ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Airway Inflammation ◽  
Critical Role ◽  
Syncytial Virus

scholarly journals Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection

2020 ◽  
Vol 11 ◽  
Author(s):  
Sandra Axberg Pålsson ◽  
Aleksandra Dondalska ◽  
Joseph Bergenstråhle ◽  
Caroline Rolfes ◽  
Albin Björk ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Antiviral Activity ◽  
Antiviral Treatment ◽  
Lung Epithelial Cells ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections ◽  
Single Stranded Oligonucleotide

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children. Currently, there is no RSV vaccine or universally accessible antiviral treatment available. Addressing the urgent need for new antiviral agents, we have investigated the capacity of a non-coding single-stranded oligonucleotide (ssON) to inhibit RSV infection. By utilizing a GFP-expressing RSV, we demonstrate that the ssON significantly reduced the proportion of RSV infected A549 cells (lung epithelial cells). Furthermore, we show that ssON’s antiviral activity was length dependent and that both RNA and DNA of this class of oligonucleotides have antiviral activity. We reveal that ssON inhibited RSV infection by competing with the virus for binding to the cellular receptor nucleolin in vitro. Additionally, using a recombinant RSV that expresses luciferase we show that ssON effectively blocked RSV infection in mice. Treatment with ssON in vivo resulted in the upregulation of RSV-induced interferon stimulated genes (ISGs) such as Stat1, Stat2, Cxcl10, and Ccl2. This study highlights the possibility of using oligonucleotides as therapeutic agents against RSV infection. We demonstrate that the mechanism of action of ssON is the inhibition of viral entry in vitro, likely through the binding of the receptor, nucleolin and that ssON treatment against RSV infection in vivo additionally results in the upregulation of ISGs.

scholarly journals Evaluation of the Safety and Immune Efficacy of Recombinant Human Respiratory Syncytial Virus Strain Long Live Attenuated Vaccine Candidates

2021 ◽  
Author(s):  
Li-Nan Wang ◽  
Xiang-Lei Peng ◽  
Min Xu ◽  
Yuan-Bo Zheng ◽  
Yue-Ying Jiao ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Gene Deletion ◽  
Human Respiratory Syncytial Virus ◽  
Temperature Sensitive ◽  
T7 Promoter ◽  
Vaccine Candidates ◽  
Rsv Infection ◽  
Syncytial Virus

AbstractHuman respiratory syncytial virus (RSV) infection is the leading cause of lower respiratory tract illness (LRTI), and no vaccine against LRTI has proven to be safe and effective in infants. Our study assessed attenuated recombinant RSVs as vaccine candidates to prevent RSV infection in mice. The constructed recombinant plasmids harbored (5′ to 3′) a T7 promoter, hammerhead ribozyme, RSV Long strain antigenomic cDNA with cold-passaged (cp) mutations or cp combined with temperature-sensitive attenuated mutations from the A2 strain (A2cpts) or further combined with SH gene deletion (A2cptsΔSH), HDV ribozyme (δ), and a T7 terminator. These vectors were subsequently co-transfected with four helper plasmids encoding N, P, L, and M2-1 viral proteins into BHK/T7-9 cells, and the recovered viruses were then passaged in Vero cells. The rescued recombinant RSVs (rRSVs) were named rRSV-Long/A2cp, rRSV-Long/A2cpts, and rRSV-Long/A2cptsΔSH, respectively, and stably passaged in vitro, without reversion to wild type (wt) at sites containing introduced mutations or deletion. Although rRSV-Long/A2cpts and rRSV-Long/A2cptsΔSH displayed  temperature-sensitive (ts) phenotype in vitro and in vivo, all rRSVs were significantly attenuated in vivo. Furthermore, BALB/c mice immunized with rRSVs produced Th1-biased immune response, resisted wtRSV infection, and were free from enhanced respiratory disease. We showed that the combination of ΔSH with attenuation (att) mutations of cpts contributed to improving att phenotype, efficacy, and gene stability of rRSV. By successfully introducing att mutations and SH gene deletion into the RSV Long parent and producing three rRSV strains, we have laid an important foundation for the development of RSV live attenuated vaccines.

scholarly journals Extracellular amoebal-vesicles: potential transmission vehicles for respiratory viruses

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Rafik Dey ◽  
Melanie A. Folkins ◽  
Nicholas J. Ashbolt
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Respiratory Viruses ◽  
Environmental Persistence ◽  
Viral Dissemination ◽  
Acute Respiratory Tract Infections ◽  
High Concentrations ◽  
Syncytial Virus ◽  
Tract Infections

AbstractHuman respiratory syncytial virus (RSV) is a major cause of acute respiratory tract infections in children and immunocompromised adults worldwide. Here we report that amoebae-release respirable-sized vesicles containing high concentrations of infectious RSV that persisted for the duration of the experiment. Given the ubiquity of amoebae in moist environments, our results suggest that extracellular amoebal-vesicles could contribute to the environmental persistence of respiratory viruses, including potential resistance to disinfection processes and thereby offering novel pathways for viral dissemination and transmission.

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