Priming with respiratory bacteria alters the airway epithelial response to subsequent viral infection

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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Viral Infection Modulates Airway Epithelial Responsiveness To Subsequent Bacterial Infection

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a3827 ◽

2010 ◽

Author(s):

John Y. Li ◽

Chad R. Morris ◽

Zhi-Qing Qi ◽

Yambasu A. Brewah ◽

Alison A. Humbles ◽

...

Keyword(s):

Bacterial Infection ◽

Viral Infection ◽

Airway Epithelial

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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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Exposure to common respiratory bacteria alters the airway epithelial response to subsequent viral infection

Respiratory Research ◽

10.1186/s12931-016-0382-z ◽

2016 ◽

Vol 17 (1) ◽

Cited By ~ 26

Author(s):

Carla Bellinghausen ◽

Fahad Gulraiz ◽

Alexandra C. A. Heinzmann ◽

Mieke A. Dentener ◽

Paul H. M. Savelkoul ◽

...

Keyword(s):

Viral Infection ◽

Airway Epithelial

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Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response

10.1101/2020.07.28.226092 ◽

2020 ◽

Author(s):

Arunima Purkayastha ◽

Chandani Sen ◽

Gustavo Garcia ◽

Justin Langerman ◽

Preethi Vijayaraj ◽

...

Keyword(s):

Viral Infection ◽

Cigarette Smoke ◽

Smoke Exposure ◽

Disease Spread ◽

Interferon Response ◽

Cigarette Smoke Exposure ◽

Airway Epithelial ◽

Airway Injury ◽

Increased Risk ◽

Airway Cells

SUMMARYMost demographic studies are now associating current smoking status with increased risk of severe COVID-19 and mortality from the disease but there remain many questions about how direct cigarette smoke exposure affects SARS-CoV-2 airway cell infection. We directly exposed mucociliary air-liquid interface (ALI) cultures derived from primary human nonsmoker airway basal stem cells (ABSCs) to short term cigarette smoke and infected them with live SARS-CoV-2. We found an increase in the number of infected airway cells after cigarette smoke exposure as well as an increased number of apoptotic cells. Cigarette smoke exposure alone caused airway injury that resulted in an increased number of ABSCs, which proliferate to repair the airway. But we found that acute SARS-CoV-2 infection or the combination of exposure to cigarette smoke and SARS-CoV-2 did not induce ABSC proliferation. We set out to examine the underlying mechanism governing the increased susceptibility of cigarette smoke exposed ALI to SARS-CoV-2 infection. Single cell profiling of the cultures showed that infected airway cells displayed a global reduction in gene expression across all airway cell types. Interestingly, interferon response genes were induced in SARS-CoV-2 infected airway epithelial cells in the ALI cultures but smoking exposure together with SARS-CoV-2 infection reduced the interferon response. Treatment of cigarette smoke-exposed ALI cultures with Interferon β-1 abrogated the viral infection, suggesting that the lack of interferon response in the cigarette smoke-exposed ALI cultures allows for more severe viral infection and cell death. In summary, our data show that acute smoke exposure allows for more severe proximal airway epithelial disease from SARS-CoV-2 by reducing the mucosal innate immune response and ABSC proliferation and has implications for disease spread and severity in people exposed to cigarette smoke.

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Faculty Opinions recommendation of Airway epithelial versus immune cell Stat1 function for innate defense against respiratory viral infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1123775.580855 ◽

2008 ◽

Author(s):

Charles Czuprynski

Keyword(s):

Viral Infection ◽

Immune Cell ◽

Airway Epithelial ◽

Respiratory Viral Infection ◽

Innate Defense

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

10.17077/etd.m1aiqczb ◽

2012 ◽

Author(s):

David Derrick Dickey

Keyword(s):

Epithelial Cells ◽

Viral Infection ◽

Airway Epithelial Cells ◽

Airway Epithelial

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Airway Epithelial versus Immune Cell Stat1 Function for Innate Defense against Respiratory Viral Infection

The Journal of Immunology ◽

10.4049/jimmunol.180.5.3319 ◽

2008 ◽

Vol 180 (5) ◽

pp. 3319-3328 ◽

Cited By ~ 56

Author(s):

Laurie P. Shornick ◽

Audrey G. Wells ◽

Yong Zhang ◽

Anand C. Patel ◽

Guangming Huang ◽

...

Keyword(s):

Viral Infection ◽

Immune Cell ◽

Airway Epithelial ◽

Respiratory Viral Infection ◽

Innate Defense

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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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