Lack of Type I Interferon Signaling Ameliorates Respiratory Syncytial Virus-Induced Lung Inflammation and Restores Antioxidant Defenses

Respiratory syncytial virus (RSV) infection in mouse and human lung is associated with pathogenic inflammation and oxidative injury. RSV impairs antioxidant responses by increasing the degradation of transcription factor NF-E2-related factor 2 (NRF2), which controls the expression of several antioxidant enzymes (AOEs). In addition to its protective effects, type I IFNs have been increasingly recognized as important mediators of host pathogenic responses during acute respiratory viral infections. We used a mouse model of RSV infection to investigate the effect of lack of type I interferon (IFN) receptor on viral-mediated clinical disease, airway inflammation, NRF2 expression, and antioxidant defenses. In the absence of type I IFN signaling, RSV-infected mice showed significantly less body weight loss and airway obstruction, as well as a significant reduction in cytokine and chemokine secretion and airway inflammation. Lack of type I IFN receptor was associated with greatly reduced virus-induced promyelocytic leukemia lung protein expression, which we showed to be necessary for virus-induced NRF2 degradation in a cell model of infection, resulting in restoration of NRF2 levels, AOE expression, and airway antioxidant capacity. Our data support the concept that modulation of type I IFN production and/or signaling could represent an important therapeutic strategy to ameliorate severity of RSV-induced lung disease.

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Plasmacytoid Dendritic Cells Contribute to the Production of IFN-β via TLR7-MyD88-Dependent Pathway and CTL Priming during Respiratory Syncytial Virus Infection

Viruses ◽

10.3390/v11080730 ◽

2019 ◽

Vol 11 (8) ◽

pp. 730 ◽

Cited By ~ 3

Author(s):

Tae Hoon Kim ◽

Dong Sun Oh ◽

Hi Eun Jung ◽

Jun Chang ◽

Heung Kyu Lee

Keyword(s):

Dendritic Cells ◽

Respiratory Syncytial Virus ◽

Type I Interferon ◽

Yellow Fluorescent Protein ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Antigen Specificity ◽

Interferon Β ◽

Rsv Infection ◽

Syncytial Virus

Respiratory syncytial virus (RSV) is the leading cause of respiratory viral infection in infants and children, yet little is known about the antiviral response of plasmacytoid dendritic cells (pDCs) to RSV infection. We tracked the cellular source of interferon-β using interferon-β/yellow fluorescent protein (YFP) reporter mice and identified the signaling pathway activated by RSV that induces type I interferon production in pDCs and DCs. Results from in vitro analyses of RSV-stimulated bone marrow cells revealed that RSV induces interferon-β production in both pDCs and DCs. Kinetic analyses of interferon-β-producing cells in RSV-infected lung cells in vivo indicated that pDCs are rapidly recruited to sites of inflammation during infection. These cells produced interferon-β via the TLR7-MyD88-mediated pathway and IFNα1R-mediated pathway rather than the MAVS-mediated pathway. Moreover, pDC-ablated mice exhibited decreased interferon-γ production and the antigen specificity of CD8+ T cells. Collectively, these data indicate that pDCs play pivotal roles in cytotoxic T lymphocyte (CTL) responses and are one of producers of type I interferon during RSV infection.

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Differential Type I Interferon Induction by Respiratory Syncytial Virus and Influenza A Virus In Vivo

Journal of Virology ◽

10.1128/jvi.00530-07 ◽

2007 ◽

Vol 81 (18) ◽

pp. 9790-9800 ◽

Cited By ~ 113

Author(s):

Nancy A. Jewell ◽

Negin Vaghefi ◽

Sara E. Mertz ◽

Parvis Akter ◽

R. Stokes Peebles ◽

...

Keyword(s):

Influenza Virus ◽

Respiratory Syncytial Virus ◽

Virus Infection ◽

Influenza A Virus ◽

Influenza A ◽

Type I Interferon ◽

Type I ◽

Type I Ifn ◽

Syncytial Virus

ABSTRACTType I interferon (IFN) induction is an immediate response to virus infection, and very high levels of these cytokines are produced when the Toll-like receptors (TLRs) expressed at high levels by plasmacytoid dendritic cells (pDCs) are triggered by viral nucleic acids. Unlike many RNA viruses, respiratory syncytial virus (RSV) does not appear to activate pDCs through their TLRs and it is not clear how this difference affects IFN-α/β induction in vivo. In this study, we investigated type I IFN production triggered by RSV or influenza A virus infection of BALB/c mice and found that while both viruses induced IFN-α/β production by pDCs in vitro, only influenza virus infection could stimulate type I IFN synthesis by pDCs in vivo. In situ hybridization studies demonstrated that the infected respiratory epithelium was a major source of IFN-α/β in response to either infection, but in pDC-depleted animals only type I IFN induction by influenza virus was impaired.

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The NS2 Protein of Human Respiratory Syncytial Virus Suppresses the Cytotoxic T-Cell Response as a Consequence of Suppressing the Type I Interferon Response

Journal of Virology ◽

10.1128/jvi.00181-06 ◽

2006 ◽

Vol 80 (12) ◽

pp. 5958-5967 ◽

Cited By ~ 30

Author(s):

Alexander Kotelkin ◽

Igor M. Belyakov ◽

Lijuan Yang ◽

Jay A. Berzofsky ◽

Peter L. Collins ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Type I Interferon ◽

Human Respiratory Syncytial Virus ◽

Interferon Response ◽

Cytotoxic T Cell ◽

Type I ◽

Type I Ifn ◽

Ifn Γ ◽

Syncytial Virus

ABSTRACT The NS1 and NS2 proteins of human respiratory syncytial virus (HRSV) have been shown to antagonize the type I interferon (IFN) response, an effect subject to host range constraints. We have now found that the HRSV NS2 protein strongly controls IFN induction in mouse cells in vitro, validating the use of the mouse model to study the consequences of these gene deletions on host immunity. We evaluated the effects of deleting the NS1 and/or NS2 gene on the induction of HRSV-specific pulmonary cytotoxic T lymphocytes (CTL) in BALB/c and 129S6 mice in response to intranasal infection with HRSV lacking the NS1 and/or NS2 gene and subsequent challenge with wild-type (wt) HRSV. In mice infected with HRSV lacking the NS2 gene (ΔNS2) or lacking the NS2 gene in combination with the NS1 gene (ΔNS1/2 HRSV), the magnitude of the pulmonary CTL response was substantially elevated compared to that of mice infected with wt HRSV or the ΔNS1 mutant, whether measured by binding of CD8+ cells to an HRSV-specific major histocompatibility complex class I tetramer, by measurement of CD8+ cells secreting gamma interferon (IFN-γ) in response to specific in vitro stimulation, or by a standard chromium release cell-killing assay. In contrast, in STAT1 knockout mice, which lack responsiveness to type I IFN, the level of IFN-γ-secreting CD8+ cells was not significantly different for HRSV lacking the NS2 gene, suggesting that the increase in CTL observed in IFN-responsive mice is type I IFN dependent. Thus, the NS2 protein of HRSV suppresses the CTL component of the adaptive immune response, and this appears to be a consequence of its suppression of type I IFN.

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Corrigendum to “Respiratory syncytial virus nonstructural protein 2 specifically inhibits type I interferon signal transduction” [Virology 344 (2006) 328–339]

Virology ◽

10.1016/j.virol.2007.07.011 ◽

2007 ◽

Vol 366 (2) ◽

pp. 453

Author(s):

Murali Ramaswamy ◽

Lei Shi ◽

Steven M. Varga ◽

Sailen Barik ◽

Mark A. Behlke ◽

...

Keyword(s):

Signal Transduction ◽

Respiratory Syncytial Virus ◽

Type I Interferon ◽

Nonstructural Protein ◽

Type I ◽

Nonstructural Protein 2 ◽

Syncytial Virus

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Differential Responses by Human Respiratory Epithelial Cell Lines to Respiratory Syncytial Virus Reflect Distinct Patterns of Infection Control

Journal of Virology ◽

10.1128/jvi.02202-17 ◽

2018 ◽

Vol 92 (15) ◽

Cited By ~ 17

Author(s):

Philippa Hillyer ◽

Rachel Shepard ◽

Megan Uehling ◽

Mina Krenz ◽

Faruk Sheikh ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Epithelial Cell ◽

Epithelial Cells ◽

Cell Lines ◽

A549 Cells ◽

Type I ◽

Epithelial Cell Lines ◽

Rsv Infection ◽

Syncytial Virus ◽

Respiratory Epithelial

ABSTRACT Respiratory syncytial virus (RSV) infects small foci of respiratory epithelial cells via infected droplets. Infection induces expression of type I and III interferons (IFNs) and proinflammatory cytokines, the balance of which may restrict viral replication and affect disease severity. We explored this balance by infecting two respiratory epithelial cell lines with low doses of recombinant RSV expressing green fluorescent protein (rgRSV). A549 cells were highly permissive, whereas BEAS-2B cells restricted infection to individual cells or small foci. After infection, A549 cells expressed higher levels of IFN-β-, IFN-λ-, and NF-κB-inducible proinflammatory cytokines. In contrast, BEAS-2B cells expressed higher levels of antiviral interferon-stimulated genes, pattern recognition receptors, and other signaling intermediaries constitutively and after infection. Transcriptome analysis revealed that constitutive expression of antiviral and proinflammatory genes predicted responses by each cell line. These two cell lines provide a model for elucidating critical mediators of local control of viral infection in respiratory epithelial cells. IMPORTANCE Airway epithelium is both the primary target of and the first defense against respiratory syncytial virus (RSV). Whether RSV replicates and spreads to adjacent epithelial cells depends on the quality of their innate immune responses. A549 and BEAS-2B are alveolar and bronchial epithelial cell lines, respectively, that are often used to study RSV infection. We show that A549 cells are permissive to RSV infection and express genes characteristic of a proinflammatory response. In contrast, BEAS-2B cells restrict infection and express genes characteristic of an antiviral response associated with expression of type I and III interferons. Transcriptome analysis of constitutive gene expression revealed patterns that may predict the response of each cell line to infection. This study suggests that restrictive and permissive cell lines may provide a model for identifying critical mediators of local control of infection and stresses the importance of the constitutive antiviral state for the response to viral challenge.

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Replication of Bovine respiratory syncytial virus in murine cells depends on type I interferon-receptor functionality

Journal of General Virology ◽

10.1099/vir.0.82091-0 ◽

2006 ◽

Vol 87 (8) ◽

pp. 2145-2148 ◽

Cited By ~ 3

Author(s):

Sabine Riffault ◽

Catherine Dubuquoy ◽

Nathalie Castagné ◽

Eric Baranowski ◽

Bernard Charley ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Cellular Level ◽

Bovine Respiratory Syncytial Virus ◽

Type I ◽

Type I Ifn ◽

Efficient Replication ◽

Control Virus ◽

Syncytial Virus ◽

Virus Strains

Bovine respiratory syncytial virus (BRSV) is able to counteract the alpha/beta interferon (IFN-α/β)-mediated antiviral response for efficient replication in a host-specific manner. Mice models have been developed for experimental infection with human, but not bovine, respiratory syncytial virus strains. Here, it is shown that BRSV can replicate efficiently on primary cell cultures derived from type I IFN receptor-deficient, but not from wild-type IFN-competent, mice. However, BRSV infection was not enhanced in mice devoid of the type I IFN receptor. These results show that type I IFN is a major host-range determinant for infection at the cellular level, but that other factors control virus replication and pathology in vivo.

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Induction of type I interferons and interferon-inducible Mx genes during respiratory syncytial virus infection and reinfection in cotton rats

Journal of General Virology ◽

10.1099/vir.0.83294-0 ◽

2008 ◽

Vol 89 (1) ◽

pp. 261-270 ◽

Cited By ~ 30

Author(s):

Lioubov M. Pletneva ◽

Otto Haller ◽

David D. Porter ◽

Gregory A. Prince ◽

Jorge C. G. Blanco

Keyword(s):

Gene Expression ◽

Respiratory Syncytial Virus ◽

Virus Replication ◽

Surrogate Marker ◽

Type I Interferons ◽

Type I ◽

Dependent Manner ◽

Type I Ifn ◽

Syncytial Virus

Respiratory syncytial virus (RSV) is the primary cause of bronchiolitis in young children. In general, RSV is considered to be a poor inducer of type I (alpha/beta) interferons (IFNs). Measurement of active type I IFN production during infection in vivo is demanding, as multiple IFN subtypes with overlapping activities are produced. In contrast, Mx gene expression, which is tightly regulated by type I IFN expression, is easily determined. This study therefore measured Mx expression as a reliable surrogate marker of type I IFN activity during RSV infection in vivo in a cotton rat model. It was shown that expression of Mx genes was dramatically augmented in the lungs of infected animals in a dose- and virus strain-dependent manner. The expression of Mx genes in the lungs was paralleled by their induction in the nose and spleen, although in spleen no simultaneous virus gene expression was detected. Reinfection of RSV-immune animals leads to abortive virus replication in the lungs. Thus, type I IFN and Mx gene expression was triggered in reinfected animals, even though virus could not be isolated from their lungs. Furthermore, it was demonstrated that immunity to RSV wanes with time. Virus replication and Mx gene expression became more prominent with increasing intervals between primary infection and reinfection. These results highlight the role of type I IFN in modulation of the immune response to RSV.

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Host Transcription Profiles upon Primary Respiratory Syncytial Virus Infection

Journal of Virology ◽

10.1128/jvi.02220-06 ◽

2007 ◽

Vol 81 (11) ◽

pp. 5958-5967 ◽

Cited By ~ 42

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.

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