scholarly journals Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans

2018 ◽  
Vol 74 (2) ◽  
pp. 442-452 ◽  
Author(s):  
Kashyap Patel ◽  
Carl M Kirkpatrick ◽  
Keith A Nieforth ◽  
Sushmita Chanda ◽  
Qingling Zhang ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Viral Replication ◽  
Replication Inhibitor ◽  
Syncytial Virus

Respiratory syncytial virus increases IL-8 gene expression and protein release in A549 cells

1995 ◽  
Vol 269 (6) ◽  
pp. L865-L872 ◽  
Author(s):  
M. A. Fiedler ◽  
K. Wernke-Dollries ◽  
J. M. Stark
Keyword(s):  
Gene Expression ◽  
Respiratory Syncytial Virus ◽  
Viral Replication ◽  
Mrna Expression ◽  
A549 Cells ◽  
Protein Release ◽  
Tnf Alpha ◽  
Epithelial Cell Line ◽  
Airway Epithelial ◽  
Syncytial Virus

The mechanism of respiratory syncytial virus (RSV)-induced inflammation in the airways of infants and children is not fully understood. We hypothesized that RSV directly induces interleukin (IL)-8 gene expression in airway epithelial cells, independent of IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) production. Exposure of A549 cells (an airway epithelial cell line) to RSV resulted in increased IL-8 mRNA expression and IL-8 protein release from the cells as early as 2 h after treatment. Neither IL-1 beta nor TNF-alpha (mRNA or protein) were detected. Viral replication was not necessary for the effects of RSV on IL-8 mRNA expression and protein release early in the infectious process. However, sustained levels of increased IL-8 production required RSV replication. A dose-response relationship was observed between the multiplicity of infection and IL-8 production with both active and nonreplicative RSV at the 2-h time point. Both active RSV and nonreplicative RSV increased the transcriptional activity of the 1.6-kb 5' flanking region of the IL-8 gene. Neither active RSV nor nonreplicative RSV increased the stability of the IL-8 mRNA in A549 cells. We conclude that RSV increases IL-8 gene expression in A549 cells in a biphasic pattern independent of viral replication early (2 h) but dependent on viral replication late (24 h).

scholarly journals The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

2015 ◽  
Vol 90 (4) ◽  
pp. 1705-1717 ◽  
Author(s):  
K. M. McCutcheon ◽  
R. Jordan ◽  
M. E. Mawhorter ◽  
S. L. Noton ◽  
J. G. Powers ◽  
...  
Keyword(s):  
Life Cycle ◽  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Viral Replication ◽  
Airway Epithelial Cells ◽  
Therapeutic Interventions ◽  
Airway Epithelial ◽  
Antiviral Activities ◽  
Syncytial Virus ◽  
Interferon Responses

ABSTRACTHuman respiratory syncytial virus (RSV) is a single-stranded RNA virus that causes acute, and occasionally fatal, lower respiratory illness in young infants, the elderly, and immunocompromised patients. Therapeutic interventions able to cut short viral replication and quickly return the airways to normal function are needed. An understanding of antiviral activities and their effects on host defense mechanisms is important for the design of safe and effective therapy. We targeted functionally and temporally distinct steps within the viral life cycle using small-molecule RSV inhibitors and studied their antiviral activities and their effects on innate interferon responses of airway epithelial cellsin vitro. Antivirals acting upstream of RSV polymerase activity (i.e., compounds targeting the fusion protein or the nucleoprotein) reduced viral load immediately postinfection and partially attenuated interferon responses. In contrast, antivirals directed to the RSV polymerase demonstrated activity throughout the viral replication cycle and specifically modulated the RIG-I/mitochondrial antiviral signaling protein (MAVS)/TBK1/IRF3/interferon-stimulated gene (ISG) axis, causing either an upregulation or a downregulation of interferon responses, depending on the mechanism of polymerase inhibition. Notably, polymerase inhibition leading to the accumulation of abortive RNA products correlated with the amplification of interferon-stimulated genes to up to 10 times above normal infection levels. Understanding how antiviral activities and their modulation of innate immunity may affect recovery from RSV infection will help guide the development of safe and effective therapies.IMPORTANCERSV circulates seasonally, causing acute lower respiratory disease. Therapeutic interventions with efficacy throughout the viral replication cycle, rapid viral clearance, and prevention of potentially harmful inflammatory responses are desirable. Compounds targeting the RSV polymerase inhibited virus replication late in the viral life cycle and, depending on the functional domain targeted, either attenuated or amplified RIG-I and downstream interferon pathways in infected cells. These data will help guide the development of safe and effective therapies by providing new molecular evidence that the mechanism of inhibition by an antiviral compound can directly impact innate antiviral immune responses in the airway epithelium.

scholarly journals Prolonged viral replication and longitudinal viral dynamic differences among respiratory syncytial virus infected infants

2017 ◽  
Vol 82 (5) ◽  
pp. 872-880 ◽  
Author(s):  
Monica E Brint ◽  
Joshua M Hughes ◽  
Aditya Shah ◽  
Chelsea R Miller ◽  
Lisa G Harrison ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Viral Replication ◽  
Viral Dynamic ◽  
Syncytial Virus

scholarly journals Host Transcription Profiles upon Primary Respiratory Syncytial Virus Infection

2007 ◽  
Vol 81 (11) ◽  
pp. 5958-5967 ◽  
Author(s):  
Riny Janssen ◽  
Jeroen Pennings ◽  
Hennie Hodemaekers ◽  
Annemarie Buisman ◽  
Marijke van Oosten ◽  
...  
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Lymph Nodes ◽  
Viral Replication ◽  
Transcriptional Level ◽  
Type I ◽  
Lung Pathology ◽  
Transcription Profiles ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract infection in children. Severe RSV disease is related to an inappropriate immune response to RSV resulting in enhanced lung pathology which is influenced by host genetic factors. To gain insight into the early pathways of the pathogenesis of and immune response to RSV infection, we determined the transcription profiles of lungs and lymph nodes on days 1 and 3 after infection of mice. Primary RSV infection resulted in a rapid but transient innate, proinflammatory response, as exemplified by the induction of a large number of type I interferon-regulated genes and chemokine genes, genes involved in inflammation, and genes involved in antigen processing. Interestingly, this response is much stronger on day 1 than on day 3 after infection, indicating that the strong transcriptional response in the lung precedes the peak of viral replication. Surprisingly, the set of down-regulated genes was small and none of these genes displayed strong down-regulation. Responses in the lung-draining lymph nodes were much less prominent than lung responses and are suggestive of NK cell activation. Our data indicate that at time points prior to the peak of viral replication and influx of inflammatory cells, the local lung response, measured at the transcriptional level, has already dampened down. The processes and pathways induced shortly after RSV infection can now be used for the selection of candidate genes for human genetic studies of children with severe RSV infection.

scholarly journals Human respiratory syncytial virus methyl transferase: a potential antiviral target?

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 750
Author(s):  
Raj Kalkeri ◽  
Govinda Bhisetti ◽  
Nagraj Mani
Keyword(s):  
Respiratory Syncytial Virus ◽  
Viral Replication ◽  
Sequence Similarity ◽  
Human Respiratory Syncytial Virus ◽  
Methyl Transferase ◽  
Mtase Activity ◽  
Literature Reviews ◽  
Host Innate Immune Response ◽  
Syncytial Virus

Human respiratory syncytial virus (HRSV) causes bronchiolitis and pneumonia. The role of methyltransferase (MTase) activity of HRSV polymerase in viral replication is unknown. Literature reviews of similar viral MTases and homology- modeling of RSV MTase bound to GTP and S-adenosylmethionine (SAM) have shown sequence similarity and the conserved catalytic residues (K-D-K-E) and the SAM-binding (GXGXG) domain. Combined with the recent reports of the importance of 2’O methylation of viral RNAs in the host innate immune response evasion, and its proposed role in viral replication, HRSV MTase holds promise as a potential antiviral target. Further biological validation of HRSV MTase could facilitate the discovery of novel HRSV antivirals targeting MTase enzyme activity.

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