scholarly journals A Novel 5-Lipoxygenase-Activating Protein Inhibitor, AM679, Reduces Inflammation in the Respiratory Syncytial Virus-Infected Mouse Eye

2009 ◽  
Vol 16 (11) ◽  
pp. 1654-1659 ◽  
Author(s):  
Alla Musiyenko ◽  
Lucia Correa ◽  
Nicholas Stock ◽  
John H. Hutchinson ◽  
Daniel S. Lorrain ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Potent Inhibitor ◽  
Interleukin 4 ◽  
Infection Model ◽  
Human Respiratory Tract ◽  
Th2 Cell ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Significant Pathway ◽  
Viral Respiratory

ABSTRACT Respiratory syncytial virus (RSV) is an important cause of viral respiratory disease in children, and RSV bronchiolitis has been associated with the development of asthma in childhood. RSV spreads from the eye and nose to the human respiratory tract. Correlative studies of humans and direct infection studies of BALB/c mice have established the eye as a significant pathway of entry of RSV to the lung. At the same time, RSV infection of the eye produces symptoms resembling allergic conjunctivitis. Cysteinyl leukotrienes (CysLTs) are known promoters of allergy and inflammation, and the first step in their biogenesis from arachidonic acid is catalyzed by 5-lipoxygenase (5-LO) in concert with the 5-LO-activating protein (FLAP). We have recently developed a novel compound, AM679, which is a topically applied and potent inhibitor of FLAP. Here we show with the BALB/c mouse eye RSV infection model that AM679 markedly reduced the RSV-driven ocular pathology as well as the synthesis of CysLTs in the eye. In addition, AM679 decreased the production of the Th2 cell cytokine interleukin-4 but did not increase the viral load in the eye or the lung. These results suggest that FLAP inhibitors may be therapeutic for RSV-driven eye disease and possibly other inflammatory eye indications.

scholarly journals Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness

2015 ◽  
Vol 309 (3) ◽  
pp. L205-L210 ◽  
Author(s):  
Weifeng Song ◽  
Zhihong Yu ◽  
Stephen F. Doran ◽  
Namasivayam Ambalavanan ◽  
Chad Steele ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Lung Injury ◽  
Airway Hyperresponsiveness ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Infection Model ◽  
Type 2 Cytokines ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
First Time

Exposure to chlorine (Cl2) damages airway and alveolar epithelia resulting in acute lung injury and reactive airway hyperresponsiveness (AHR) to methacholine. However, little is known about the effect of preexisting respiratory disease on Cl2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1β, IL-10, IFN-γ, and RANTES concentrations in the bronchoalveolar lavage fluid (BALF). In contrast, levels of type 2 cytokines (i.e., IL-4, IL-5, IL-9, and IL-13) were not significantly affected by either RSV infection or Cl2 exposure. Cl2 exposure, but not RSV infection, induced AHR to methacholine challenge as measured by flexiVent. Moreover, preexisting RSV infection amplified BALF levels of hyaluronan (HA) and AHR. The Cl2-induced AHR was mitigated by treatment with inter-α-trypsin inhibitor antibody, which inhibits HA signaling, suggesting a mechanism of HA-mediated AHR from exacerbated oxidative injury. Our results show for the first time that preexisting RSV infection predisposes the lung to Cl2-induced injury. These data emphasize the necessity for further research on the effects of Cl2 in vulnerable populations and the development of appropriate treatments.

scholarly journals Inhibition of Human Respiratory Syncytial Virus Infectivity by a Dendrimeric Heparan Sulfate-Binding Peptide

2012 ◽  
Vol 56 (10) ◽  
pp. 5278-5288 ◽  
Author(s):  
Manuela Donalisio ◽  
Marco Rusnati ◽  
Valeria Cagno ◽  
Andrea Civra ◽  
Antonella Bugatti ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Antiviral Activity ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
A549 Cells ◽  
Epithelial Tissue ◽  
Virus Infectivity ◽  
Human Respiratory Tract ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACTRespiratory syncytial virus (RSV) interacts with cell surface heparan sulfate proteoglycans (HSPGs) to initiate infection. The interaction of RSV with HSPGs thus presents an attractive target for the development of novel inhibitors of RSV infection. In the present study, a minilibrary of linear, dimeric, and dendrimeric peptides containing clusters of basic amino acids was screened with the aim of identifying peptides able to bind HSPGs and thus block RSV attachment and infectivity. Of the compounds identified, the dendrimer SB105-A10 was the most potent inhibitor of RSV infectivity, with 50% inhibitory concentrations (IC50s) of 0.35 μM and 0.25 μM measured in Hep-2 and A549 cells, respectively. SB105-A10 was found to bind to both cell types via HSPGs, suggesting that its antiviral activity is indeed exerted by competing with RSV for binding to cell surface HSPGs. SB105-A10 prevented RSV infection when added before the viral inoculum, in line with its proposed HSPG-binding mechanism of action; moreover, antiviral activity was also exhibited when SB105-A10 was added postinfection, as it was able to reduce the cell-to-cell spread of the virus. The antiviral potential of SB105-A10 was further assessed using human-derived tracheal/bronchial epithelial cells cultured to form a pseudostratified, highly differentiated model of the epithelial tissue of the human respiratory tract. SB105-A10 strongly reduced RSV infectivity in this model and exhibited no signs of cytotoxicity or proinflammatory effects. Together, these features render SB105-A10 an attractive candidate for further development as a RSV inhibitor to be administered by aerosol delivery.

scholarly journals Chlorobenzoxime inhibits respiratory syncytial virus infection in neonatal rats via up-regulation of IFN-γ in dendritic cells

2020 ◽  
Vol 19 (2) ◽  
pp. 239-246
Author(s):  
Junzhao Li ◽  
Yonghai Zhang ◽  
Hongmei Qiao ◽  
Yingji Jin ◽  
Jianmin Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Respiratory Syncytial Virus ◽  
Neonatal Rat ◽  
Interleukin 4 ◽  
Neonatal Rats ◽  
Alveolar Cells ◽  
Rsv Infection ◽  
Ifn Γ ◽  
Syncytial Virus

Purpose: To investigate the effect of chlorobenzoxime on respiratory syncytial virus (RSV) infection in vitro in lung alveolar cells and in vivo in neonatal rats, as well as the mechanism of action involved. Methods: RSV infection in neonatal rats was induced via intranasal administration of 2 x 106PFU viral particles. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting were used for determination of changes in interleukin expression. Results: RSV infection in BEAS-2B cells caused significant reduction in viability and marked alteration in morphological appearance (p < 0.05). Exposure of RSV-infected BEAS-2B cells to chlorobenzoxime prevented viability reduction and changes in morphology, and led to reductions in RSV-mediated increases in levels of interleukin-6 and interleukin-8. Moreover, RSV infection significantly enhanced ROS levels in BEAS-2B cells, when compared to control cells (p < 0.05). Chlorobenzoxime at a concentration of 30 μM completely suppressed RSV-mediated generation of ROS in BEAS-2B cells. In neonatal rats, RSV-induced upregulation of interleukin-4, interleukin-13 and TNF-α, were suppressed in bronchoalveolar lavage fluid (BALF) and lung tissues by chlorobenzoxime. Moreover, the RSVmediated reduction in IFN-γ was maximally blocked by chlorobenzoxime at a dose of 10 mg/mL. Chlorobenzoxime enhanced the proportion of IFN-γ -producing cells in neonatal rat BALF. Conclusion: Chlorobenzoxime exhibits antiviral against RSV infection in neonatal rats via increase in dendritic cell population, leading to inhibition of cytokine production. Therefore, chlorobenzoxime is a potential therapeutic agent for RSV infection. Keywords: Respiratory syncytial virus, Cytokines, Dendritic cells, Lung aveolar cells, Morphology, Interleukins

scholarly journals Kinetics of Respiratory Syncytial Virus (RSV) Memphis Strain 37 (M37) Infection in the Respiratory Tract of Newborn Lambs as an RSV Infection Model for Human Infants

PLoS ONE ◽  
2015 ◽  
Vol 10 (12) ◽  
pp. e0143580 ◽  
Author(s):  
Alejandro Larios Mora ◽  
Laurent Detalle ◽  
Albert Van Geelen ◽  
Michael S. Davis ◽  
Thomas Stohr ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Infection Model ◽  
Human Infants ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Kinetics Of

scholarly journals Priming with a Secreted Form of the Fusion Protein of Respiratory Syncytial Virus (RSV) Promotes Interleukin-4 (IL-4) and IL-5 Production but Not Pulmonary Eosinophilia following RSV Challenge

1999 ◽  
Vol 73 (12) ◽  
pp. 10086-10094 ◽  
Author(s):  
Gary P. Bembridge ◽  
Juan A. Lopez ◽  
Regla Bustos ◽  
Jose A. Melero ◽  
Roy Cook ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
G Protein ◽  
Interleukin 4 ◽  
Soluble Form ◽  
Interferon Production ◽  
F Protein ◽  
The Face ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT The attachment (G) protein of respiratory syncytial virus (RSV) is synthesized as two mature forms: a membrane-anchored form and a smaller secreted form. BALB/c mice scarified with vaccinia virus (VV) expressing the secreted form develop a greater pulmonary eosinophilic influx following RSV challenge than do mice scarified with VV expressing the membrane-anchored form. To determine if a soluble form of an RSV protein was sufficient to induce eosinophilia following RSV challenge, a cDNA that encoded a secreted form of the fusion (F) protein of RSV was constructed and expressed in VV (VV-Ftm−). Splenocytes and lung lymphocytes from mice primed with VV-Ftm− produced significantly more of the Th2 cytokines interleukin-4 (IL-4) and IL-5 than did mice vaccinated with VV expressing either the native (membrane-anchored) form of the F protein or the G protein. Although mice scarified with VV-Ftm− developed a slight increase in the number of pulmonary eosinophils following RSV infection, the increase was not as great as that seen in VV-G-primed mice. Despite the increased IL-4 and IL-5 production and in contrast to mice primed with VV-G, mice primed with VV-Ftm− developed RSV-specific cytotoxic T lymphocytes (CTL) and maintained high levels of gamma interferon production. These data demonstrate that recombinant VV strains expressing soluble forms of RSV proteins induce immune responses that are more Th2-like. However, this change alone does not appear sufficient to induce vaccine-augmented disease in the face of active CD8+ CTL populations.

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 Respiratory Syncytial Virus Immunoprophylaxis with Palivizumab: 12-Year Observational Study of Usage and Outcomes in Canada

2021 ◽  
Author(s):  
Ian Mitchell ◽  
Abby Li ◽  
Candice L. Bjornson ◽  
Krista L. Lanctot ◽  
Bosco A. Paes ◽  
...  
Keyword(s):  
Risk Factors ◽  
Respiratory Syncytial Virus ◽  
Burden Of Illness ◽  
Respiratory Illness ◽  
Smoking Exposure ◽  
Key Points ◽  
Rsv Infection ◽  
History Of ◽  
Syncytial Virus ◽  
Airway Anomalies

Objective This study aimed to evaluate palivizumab (PVZ) use, trends in indications, and outcomes of respiratory illness hospitalizations (RIH) and respiratory syncytial virus hospitalizations (RSVH). Study Design It involves a large, Canadian prospective (2005–2017) observational multicenter study of children at high risk for RSV infection. Results A total of 25,003 infants (56.3% male) were enrolled at 32 sites; 109,579 PVZ injections were administered. Indications included: prematurity (63.3%); “miscellaneous” (17.8%); hemodynamically significant congenital heart disease (10.5%); bronchopulmonary dysplasia/chronic lung disease (8.4%). The “miscellaneous” group increased over time (4.4% in 2005–2006 to 22.5% in 2016–2017) and included: trisomy 21, airway anomalies, pulmonary disorders, cystic fibrosis, neurological impairments, immunocompromised, cardiac aged >2 years, multiple conditions, and a residual “unclassified” group. Adherence measured by expected versus actual doses plus correct interdose interval was 64.7%. A total of 2,054 RIH occurred (6.9%); 198 (9.6%) required intubation. Three hundred thirty-seven hospitalized children were RSV-positive (overall RSVH 1.6%). Risk factors for RSVH included having siblings, attending daycare, family history of atopy, smoking exposure, and crowded household. Infants with 5 risk factors were 9.0 times (95% CI or confidence interval 4.4–18.2; p < 0.0005) more likely to have RSVH than infants without risk factors. Three adverse events occurred; none were fatal. Conclusion Results are relevant to both clinicians and decision-makers. We confirmed the safety of PVZ. Use of PVZ increased steadily for children with miscellaneous conditions and medical complexity. Medical and social factors pose a risk for severe RIH and RSVH with accompanying burden of illness. A vaccine that protects against RSV is urgently required. Key Points

scholarly journals Respiratory syncytial virus in severe lower respiratory infections in previously healthy young Ethiopian infants

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Abate Yeshidinber Weldetsadik ◽  
Frank Riedel
Keyword(s):  
Respiratory Syncytial Virus ◽  
Rainy Season ◽  
Clinical Laboratory ◽  
Respiratory Infections ◽  
Clinical Parameter ◽  
Imaging Data ◽  
Chi Square ◽  
Young Infants ◽  
Rsv Infection ◽  
Syncytial Virus

Abstract Background Respiratory Syncytial Virus (RSV) is the commonest cause of acute lower respiratory infections (ALRI) in infants. However, the burden of RSV is unknown in Ethiopia. We aimed to determine the prevalence, seasonality and predictors of RSV infection in young infants with ALRI for the first time in Ethiopia. Methods We performed RSV immuno-chromatographic assay from nasopharyngeal swabs of infants, 29 days to 6 months of age. We included the first 10 eligible infants in each month from June 2018 to May 2019 admitted in a tertiary pediatric center. Clinical, laboratory and imaging data were also collected, and chi-square test and regression were used to assess associated factors with RSV infection. Results Among a total of 117 study children, 65% were male and mean age was 3 months. Bronchiolitis was the commonest diagnosis (49%). RSV was isolated from 26 subjects (22.2%) of all ALRI, 37% of bronchiolitis and 11% of pneumonia patients. Although RSV infection occurred year round, highest rate extended from June to November. No clinical or laboratory parameter predicted RSV infection and only rainy season (Adjusted Odds Ratio (AOR) 10.46 [95%. C.I. 1.95, 56.18]) was independent predictor of RSV infection. Conclusions RSV was isolated in a fifth of young infants with severe ALRI, mostly in the rainy season. Diagnosis of RSV infection in our setting require specific tests as no clinical parameter predicted RSV infection. Since RSV caused less than a quarter of ALRI in our setting, the other causes should be looked for in future studies.

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