scholarly journals The Role of Toll-like receptor 4 in respiratory syncytial virus replication, interferon lambda 1 induction, and chemokine responses

2018 ◽  
Author(s):  
Lindsay Broadbent ◽  
Jonathon D. Coey ◽  
Michael D. Shields ◽  
Ultan F. Power
Keyword(s):  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Virus Replication ◽  
Growth Kinetics ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Pro Inflammatory Cytokines

AbstractRespiratory syncytial virus (RSV) infection is the leading cause of severe lower respiratory tract infections (LRTI) in infants worldwide. The immune responses to RSV infection are implicated in RSV pathogenesis but RSV immunopathogenesis in humans remains poorly understood. We previously demonstrated that IFN-λ1 is the principle interferon induced following RSV infection of infants and well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs). Interestingly, RSV F interacts with the TLR4/CD14/MD2 complex to initiate secretion of pro-inflammatory cytokines, while TLR4 stimulation with house dust mite induces IFN-λ1 production. However, the role of TLR4 in RSV infection and concomitant IFN-λ1 induction remains unclear. Using our RSV/WD-PBEC infection model, we found that CLI-095 inhibition of TLR4 resulted in significantly reduced viral growth kinetics, and secretion of IFN-λ1 and pro-inflammatory chemokines. To elucidate specific TLR4 signalling intermediates implicated in virus replication and innate immune responses we selected 4 inhibitors, including LY294002, U0126, SB203580 and JSH-23. SB203580, a p38 MAPK inhibitor, reduced both viral growth kinetics and IFN-λ1 secretion, while JSH-23, an NF-κB inhibitor, reduced IFN-λ1 secretion without affecting virus growth kinetics. Our data indicate that TLR4 plays a role in RSV entry and/or replication and IFN-λ1 induction following RSV infection is mediated, in part, by TLR4 signalling through NF- κB and/or p38 MAPK. Therefore, targeting TLR4 or downstream effector proteins could present novel treatment strategies against RSV.ImportanceThe role of TLR4 in RSV infection and IFN-λ1 induction is controversial. Using our WD-PBEC model, which replicates many hallmarks of RSV infection in vivo, we demonstrated that the TLR4 pathway is involved in both RSV infection and/or replication and the concomitant induction of IFN-λ1 and other pro-inflammatory cytokines. Increasing our understanding of the role of TLR4 in RSV immunopathogenesis may lead to the development of novel RSV therapeutics.

RESPIRATORY SYNCYTIAL VIRUS LUNG INFECTION IN INFANTS: IMMUNOREGULATORY ROLE OF INFECTED ALVEOLAR MACROPHAGES

PEDIATRICS ◽  
1995 ◽  
Vol 96 (2) ◽  
pp. 391-391
Author(s):  
Leon S. Greos
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Lung Infection ◽  
Local Immune Response ◽  
Rsv Infection ◽  
Syncytial Virus

Alveolar macrophages are infected by RSV in vivo and coexpress potent immunomodulatory molecules that potentially regulate local immune response or lung injury caused by RSV infection.

scholarly journals Original Antigenic Sin and Respiratory Syncytial Virus Vaccines

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 107 ◽  
Author(s):  
Ralph A. Tripp ◽  
Ultan F. Power
Keyword(s):  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
Vaccine Efficacy ◽  
Potential Role ◽  
Memory Response ◽  
Hierarchical Nature ◽  
Syncytial Virus ◽  
Negative Impacts ◽  
Original Antigenic Sin

The original antigenic sin (OAS) theory considers the outcome of the first encounter with an antigen. It favors a memory response to the original antigen upon exposure to a similar or related antigen, and includes both positive and negative impacts of past exposure on the memory response to challenge, and, in particular, on vaccine efficacy. This phenomenon is closely linked with imprinting and the hierarchical nature of immune responses to previously encountered antigens. The focus of this commentary centers on the potential role of OAS or immunological imprinting on respiratory syncytial virus memory responses.

Role of p38 MAPK and pro‐inflammatory cytokines expression in glutamate‐induced neuronal death of neonatal rats

2008 ◽  
Vol 26 (5) ◽  
pp. 487-495 ◽  
Author(s):  
V. Chaparro‐Huerta ◽  
M.E. Flores‐Soto ◽  
G. Gudiño‐Cabrera ◽  
M.C. Rivera‐Cervantes ◽  
O.K. Bitzer‐Quintero ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Neuronal Death ◽  
Neonatal Rats ◽  
Pro Inflammatory Cytokines

scholarly journals Central Role of the NF-κB Pathway in theScgb1a1-Expressing Epithelium in Mediating Respiratory Syncytial Virus-Induced Airway Inflammation

2018 ◽  
Vol 92 (11) ◽  
Author(s):  
Bing Tian ◽  
Jun Yang ◽  
Yingxin Zhao ◽  
Teodora Ivanciuc ◽  
Hong Sun ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Lower Respiratory Tract ◽  
Pol Ii ◽  
Neutrophilic Inflammation ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Epithelial Cell Population

ABSTRACTLower respiratory tract infection with respiratory syncytial virus (RSV) produces profound inflammation. Despite an understanding of the role of adaptive immunity in RSV infection, the identity of the major sentinel cells initially triggering inflammation is controversial. Here we evaluate the role of nonciliated secretoglobin (Scgb1a1)-expressing bronchiolar epithelial cells in RSV infection. Mice expressing a tamoxifen (TMX)-inducible Cre recombinase-estrogen receptor fusion protein (CreERTM) knocked into theScgb1a1locus were crossed with mice that harbor aRelAconditional allele (RelAfl), with loxP sites flanking exons 5 to 8 of the Rel homology domain. TheScgb1a1CreERTM/+× RelAfl/flmouse is aRelAconditional knockout (RelACKO) of a nonciliated epithelial cell population enriched in the small bronchioles. TMX-treated RelACKOmice have reduced pulmonary neutrophilic infiltration and impaired expression and secretion of NF-κB-dependent cytokines in response to RSV. In addition, RelACKOmice had reduced expression levels of interferon (IFN) regulatory factor 1/7 (IRF1/7) and retinoic acid-inducible gene I (RIG-I), components of the mucosal IFN positive-feedback loop. We demonstrate that RSV replication induces RelA to complex with bromodomain-containing protein 4 (BRD4), a cofactor required for RNA polymerase II (Pol II) phosphorylation, activating the atypical histone acetyltransferase (HAT) activity of BRD4 required for phospho-Ser2 Pol II formation, histone H3K122 acetylation, and cytokine secretionin vitroandin vivo. TMX-treated RelACKOmice have less weight loss and reduced airway obstruction/hyperreactivity yet similar levels of IFN-γ production despite higher levels of virus production. These data indicate that the nonciliatedScgb1a1-expressing epithelium is a major innate sensor for restricting RSV infection by mediating neutrophilic inflammation and chemokine and mucosal IFN production via the RelA-BRD4 pathway.IMPORTANCERSV infection is the most common cause of infant hospitalizations in the United States, resulting in 2.1 million children annually requiring medical attention. RSV primarily infects nasal epithelial cells, spreading distally to produce severe lower respiratory tract infections. Our study examines the role of a nonciliated respiratory epithelial cell population in RSV infection. We genetically engineered a mouse that can be selectively depleted of the NF-κB/RelA transcription factor in this subset of epithelial cells. These mice show an impaired activation of the bromodomain-containing protein 4 (BRD4) coactivator, resulting in reduced cytokine expression and neutrophilic inflammation. During the course of RSV infection, epithelial RelA-depleted mice have reduced disease scores and airway hyperreactivity yet increased levels of virus replication. We conclude that RelA-BRD4 signaling in nonciliated bronchiolar epithelial cells mediates neutrophilic airway inflammation and disease severity. This complex is an attractive target to reduce the severity of infection.

The Role of Notch-Notch Ligand Signaling in Primary and Secondary Respiratory Syncytial Virus (RSV) Infection

2011 ◽  
Vol 127 (2) ◽  
pp. AB147-AB147
Author(s):  
J. Han ◽  
M. Okamoto ◽  
K. Takeda ◽  
K. Yasutomo ◽  
E.W. Gelfand
Keyword(s):  
Respiratory Syncytial Virus ◽  
Notch Ligand ◽  
Rsv Infection ◽  
Syncytial Virus

scholarly journals Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection

2005 ◽  
Vol 18 (3) ◽  
pp. 541-555 ◽  
Author(s):  
Peter J. M. Openshaw ◽  
John S. Tregoning
Keyword(s):  
Respiratory Syncytial Virus ◽  
Animal Models ◽  
Immune Responses ◽  
Deep Understanding ◽  
T Cell Subsets ◽  
Chemokine Production ◽  
Syncytial Virus ◽  
Complex Deposition ◽  
Major Factors

SUMMARY Respiratory syncytial virus (RSV) is one of the commonest and most troublesome viruses of infancy. It causes most cases of bronchiolitis, which is associated with wheezing in later childhood. In primary infection, the peak of disease typically coincides with the development of specific T- and B-cell responses, which seem, in large part, to be responsible for disease. Animal models clearly show that a range of immune responses can enhance disease severity, particularly after vaccination with formalin-inactivated RSV. Prior immune sensitization leads to exuberant chemokine production, an excessive cellular influx, and an overabundance of cytokines during RSV challenge. Under different circumstances, specific mediators and T-cell subsets and antibody-antigen immune complex deposition are incriminated as major factors in disease. Animal models of immune enhancement permit a deep understanding of the role of specific immune responses in RSV disease, assist in vaccine design, and indicate which immunomodulatory therapy might be beneficial to children with bronchiolitis.

scholarly journals Treatment with respiratory syncytial virus G glycoprotein monoclonal antibody or F(ab′)2 components mediates reduced pulmonary inflammation in mice

2009 ◽  
Vol 90 (5) ◽  
pp. 1119-1123 ◽  
Author(s):  
Congrong Miao ◽  
Gertrud U. Radu ◽  
Hayat Caidi ◽  
Ralph A. Tripp ◽  
Larry J. Anderson ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Respiratory Syncytial Virus ◽  
Interferon Gamma ◽  
Virus Replication ◽  
Pulmonary Inflammation ◽  
Leukocyte Trafficking ◽  
Virus Clearance ◽  
Neutralizing Monoclonal Antibody ◽  
Rsv Infection ◽  
Syncytial Virus

Therapeutic treatment with a non-neutralizing monoclonal antibody (mAb) (131-2G) specific to respiratory syncytial virus (RSV) G glycoprotein mediates virus clearance and decreases leukocyte trafficking and interferon gamma (IFN-γ) production in the lungs of RSV-infected mice. Its F(ab′)2 component only mediates decreased leukocyte trafficking and IFN-γ production without reducing virus replication. Thus, this mAb has two independent actions that could facilitate treatment and/or prevention of RSV infection by reducing both virus replication and virus-induced pulmonary inflammation.

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