Strategies for improving adeno-associated viral infection of airway epithelial cells

Airway epithelial cells are the primary cell type involved in respiratory viral infection. Upon infection, airway epithelium plays a critical role in host defense against viral infection by contributing to innate and adaptive immune responses. Influenza A virus, rhinovirus, and respiratory syncytial virus (RSV) represent a broad range of human viral pathogens that cause viral pneumonia and induce exacerbations of asthma and chronic obstructive pulmonary disease. These respiratory viruses induce airway epithelial production of IL-8, which involves epidermal growth factor receptor (EGFR) activation. EGFR activation involves an integrated signaling pathway that includes NADPH oxidase activation of metalloproteinase, and EGFR proligand release that activates EGFR. Because respiratory viruses have been shown to activate EGFR via this signaling pathway in airway epithelium, we investigated the effect of virus-induced EGFR activation on airway epithelial antiviral responses. CXCL10, a chemokine produced by airway epithelial cells in response to respiratory viral infection, contributes to the recruitment of lymphocytes to target and kill virus-infected cells. While respiratory viruses activate EGFR, the interaction between CXCL10 and EGFR signaling pathways is unclear, and the potential for EGFR signaling to suppress CXCL10 has not been explored. Here, we report that respiratory virus-induced EGFR activation suppresses CXCL10 production. We found that influenza virus-, rhinovirus-, and RSV-induced EGFR activation suppressed IFN regulatory factor (IRF) 1-dependent CXCL10 production. In addition, inhibition of EGFR during viral infection augmented IRF1 and CXCL10. These findings describe a novel mechanism that viruses use to suppress endogenous antiviral defenses, and provide potential targets for future therapies.

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Virus Infection-Induced Bronchial Asthma Exacerbation

Pulmonary Medicine ◽

10.1155/2012/834826 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 26

Author(s):

Mutsuo Yamaya

Keyword(s):

Epithelial Cells ◽

Viral Infection ◽

Airway Inflammation ◽

Bronchial Asthma ◽

Inflammatory Mediators ◽

Asthma Exacerbation ◽

Viral Infections ◽

Inflammatory Cells ◽

Airway Epithelial Cells ◽

Airway Epithelial

Infection with respiratory viruses, including rhinoviruses, influenza virus, and respiratory syncytial virus, exacerbates asthma, which is associated with processes such as airway inflammation, airway hyperresponsiveness, and mucus hypersecretion. In patients with viral infections and with infection-induced asthma exacerbation, inflammatory mediators and substances, including interleukins (ILs), leukotrienes and histamine, have been identified in the airway secretions, serum, plasma, and urine. Viral infections induce an accumulation of inflammatory cells in the airway mucosa and submucosa, including neutrophils, lymphocytes and eosinophils. Viral infections also enhance the production of inflammatory mediators and substances in airway epithelial cells, mast cells, and other inflammatory cells, such as IL-1, IL-6, IL-8, GM-CSF, RANTES, histamine, and intercellular adhesion molecule-1. Viral infections affect the barrier function of the airway epithelial cells and vascular endothelial cells. Recent reports have demonstrated augmented viral production mediated by an impaired interferon response in the airway epithelial cells of asthma patients. Several drugs used for the treatment of bronchial asthma reduce viral and pro-inflammatory cytokine release from airway epithelial cells infected with viruses. Here, I review the literature on the pathogenesis of the viral infection-induced exacerbation of asthma and on the modulation of viral infection-induced airway inflammation.

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Regulation of RANTES promoter activation in alveolar epithelial cells after cytokine stimulation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00162.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. L1280-L1290 ◽

Cited By ~ 44

Author(s):

Antonella Casola ◽

Allyne Henderson ◽

Tianshuang Liu ◽

Roberto P. Garofalo ◽

Allan R. Brasier

Keyword(s):

Gene Expression ◽

Epithelial Cells ◽

Viral Infection ◽

Molecular Mechanisms ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Mrna Stabilization ◽

Tnf Α ◽

Ifn Γ ◽

Responsive Element

Regulated on activation, normal T cell expressed, and presumably secreted (RANTES) is a member of the CC chemokine family of proteins implicated in a variety of diseases characterized by lung eosinophilia and inflammation, strongly produced by stimulated airway epithelial cells. Because such cytokines as tumor necrosis factor (TNF)-α and interferon-γ (IFN-γ) have been shown to enhance RANTES induction in airway epithelial cells and RANTES gene expression appears to be differentially regulated depending on the cell type and the stimulus applied, in this study we have elucidated mechanisms that operate to control RANTES induction on exposure to TNF-α and/or IFN-γ. Our results indicate that TNF-α and IFN-γ synergistically induce RANTES protein secretion and mRNA expression. RANTES transcription is activated only after stimulation with TNF-α, but not IFN-γ, which affects RANTES mRNA stabilization. Promoter deletion and mutagenesis experiments indicate that the nuclear factor (NF)-κB site is the most important cis-regulatory element controlling TNF-induced RANTES transcription, although NF-interleukin-6 binding site, cAMP responsive element (CRE), and interferon-stimulated responsive element (ISRE) also play a significant role. TNF-α stimulation induces nuclear translocation of interferon regulatory factor (IRF)-3, which in viral infection binds the RANTES ISRE and is necessary for activation of RANTES transcription. However, TNF-induced IRF-3 translocation does not result in IRF-3 binding to the RANTES ISRE. Although viral infection can activate an ISRE-driven promoter, TNF cannot, indicating that RANTES gene enhancers are controlled in a stimulus-specific fashion. Identification of molecular mechanisms involved in RANTES gene expression is fundamental for developing strategies to modulate lung inflammatory responses.

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Inhibition of Virus-Induced Cytokine Production from Airway Epithelial Cells by the Late Addition of Budesonide

Medicina ◽

10.3390/medicina56030098 ◽

2020 ◽

Vol 56 (3) ◽

pp. 98 ◽

Cited By ~ 2

Author(s):

Tetsuya Homma ◽

Yosuke Fukuda ◽

Yoshitaka Uchida ◽

Tomoki Uno ◽

Megumi Jinno ◽

...

Keyword(s):

Epithelial Cells ◽

Viral Infection ◽

Inflammatory Cells ◽

Airway Epithelial Cells ◽

Thymic Stromal Lymphopoietin ◽

Allergic Airway Disease ◽

Poly I:C ◽

Enzyme Linked Immunosorbent Assay ◽

Chronic Obstructive ◽

Airway Epithelial

Background and objectives: Viral infection is the main cause of asthma and COPD (chronic obstructive pulmonary disease) exacerbation and accumulate inflammatory cells to airway tissue. We have reported poly I:C, a mimic product of the virus and ligand of toll-like receptor 3 (TLR3), induced inflammatory chemokines from airway epithelial cells and found prior incubation with corticosteroids diminishes the effect of TLR3 activation. In clinical practice, mild asthma is recommended as-needed budesonide (BUD) when symptoms occur following a viral infection, etc. However, many questions still surround BUD’s usefulness if taken after a virus has already infected airway tissue. The aim of this study was to investigate the inhibitory effects of BUD on inflammatory cytokines induced by viral infection. Materials and Methods: Normal human bronchial epithelial (NHBE) cells were stimulated with poly I:C or infected with human rhinovirus-16 (HRV16) and BUD was added after the initial stimulation. Expression of both thymic stromal lymphopoietin (TSLP) and CCL26/eotaxin-3 was quantified by real-time RT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Knockdown study was performed. Results: Pre-or post-incubation with BUD inhibited both poly I:C- and HRV16-induced mRNAs and proteins of both thymic stromal lymphopoietin (TSLP) and CCL26 with significance. Knockdown of the glucocorticoid receptor diminished these effects of BUD. Under the same conditions of BUD’s experiment, post-incubation with neither fluticasone propionate nor dexamethasone suppressed expression of both TSLP and CCL26, which induced by poly I:C. Conclusion: Post-addition of BUD inhibited the virus-induced TSLP and CCL26 from the airway epithelial cells. These results suggest that inhalation of BUD after viral infection has beneficial effects on asthma. Conclusion: Late addition of BUD may benefit among patient with viral infection and type 2 allergic airway disease such as asthma.

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Effect of Nitrogen Dioxide on Respiratory Viral Infection in Airway Epithelial Cells

Environmental Research ◽

10.1006/enrs.1999.3963 ◽

1999 ◽

Vol 81 (2) ◽

pp. 159-166 ◽

Cited By ~ 28

Author(s):

Susanne Becker ◽

Joleen M. Soukup

Keyword(s):

Epithelial Cells ◽

Viral Infection ◽

Nitrogen Dioxide ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Respiratory Viral Infection

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Consequences of Respiratory Viral Infection in Airway Epithelial Cells

Respiratory Infections in Allergy and Asthma ◽

10.1201/9780203911761.ch7 ◽

2003 ◽

Author(s):

Susanne Becker ◽

Frederick Henderson

Keyword(s):

Epithelial Cells ◽

Viral Infection ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Respiratory Viral Infection

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Asthmatic airway epithelial cells subjected to apical mechanical stress exhibit suppressed interferon release following viral infection

10.1183/13993003.congress-2019.pa3337 ◽

2019 ◽

Author(s):

Punnam Chander Veerati ◽

Andrew Reid ◽

Kristy Nichol ◽

Peter Wark ◽

Nathan Bartlett ◽

...

Keyword(s):

Epithelial Cells ◽

Viral Infection ◽

Mechanical Stress ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Asthmatic Airway

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ORMDL3 regulates poly I:C induced inflammatory responses in airway epithelial cells

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01496-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Gemma Laura ◽

Yi Liu ◽

Kieran Fernandes ◽

Saffron A. G. Willis-Owen ◽

Kazuhiro Ito ◽

...

Keyword(s):

Epithelial Cells ◽

Inflammatory Response ◽

Viral Infection ◽

Airway Epithelial Cells ◽

Poly I:C ◽

Synthetic Analog ◽

Mrna Levels ◽

Airway Epithelial ◽

Over Expression ◽

Polycytidylic Acid

Abstract Background Oroscomucoid 3 (ORMDL3) has been linked to susceptibility of childhood asthma and respiratory viral infection. Polyinosinic-polycytidylic acid (poly I:C) is a synthetic analog of viral double-stranded RNA, a toll-like receptor 3 (TLR3) ligand and mimic of viral infection. Methods To investigate the functional role of ORMDL3 in the poly I:C-induced inflammatory response in airway epithelial cells, ORMDL3 knockdown and over-expression models were established in human A549 epithelial cells and primary normal human bronchial epithelial (NHBE) cells. The cells were stimulated with poly I:C or the Th17 cytokine IL-17A. IL-6 and IL-8 levels in supernatants, mRNA levels of genes in the TLR3 pathway and inflammatory response from cell pellets were measured. ORMDL3 knockdown models in A549 and BEAS-2B epithelial cells were then infected with live human rhinovirus (HRV16) followed by IL-6 and IL-8 measurement. Results ORMDL3 knockdown and over-expression had little influence on the transcript levels of TLR3 in airway epithelial cells. Time course studies showed that ORMDL3-deficient A549 and NHBE cells had an attenuated IL-6 and IL-8 response to poly I:C stimulation. A549 and NHBE cells over-expressing ORMDL3 released relatively more IL-6 and IL-8 following poly I:C stimulation. IL-17A exhibited a similar inflammatory response in ORMDL3 knockdown and over-expressing cells, but co-stimulation of poly I:C and IL-17A did not significantly enhance the IL-6 and IL-8 response. Transcript abundance of IFNB following poly I:C stimulation was not significantly altered by ORMDL3 knockdown or over-expression. Dampening of the IL-6 response by ORMDL3 knockdown was confirmed in HRV16 infected BEAS-2B and A549 cells. Conclusions ORMDL3 regulates the viral inflammatory response in airway epithelial cells via mechanisms independent of the TLR3 pathway.

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