Deciphering Respiratory-Virus-Associated Interferon Signaling in COPD Airway Epithelium

COPD is a chronic lung disorder characterized by a progressive and irreversible airflow obstruction, and persistent pulmonary inflammation. It has become a global epidemic affecting 10% of the population, and is the third leading cause of death worldwide. Respiratory viruses are a primary cause of COPD exacerbations, often leading to secondary bacterial infections in the lower respiratory tract. COPD patients are more susceptible to viral infections and associated severe disease, leading to accelerated lung function deterioration, hospitalization, and an increased risk of mortality. The airway epithelium plays an essential role in maintaining immune homeostasis, and orchestrates the innate and adaptive responses of the lung against inhaled and pathogen insults. A healthy airway epithelium acts as the first line of host defense by maintaining barrier integrity and the mucociliary escalator, secreting an array of inflammatory mediators, and initiating an antiviral state through the interferon (IFN) response. The airway epithelium is a major site of viral infection, and the interaction between respiratory viruses and airway epithelial cells activates host defense mechanisms, resulting in rapid virus clearance. As such, the production of IFNs and the activation of IFN signaling cascades directly contributes to host defense against viral infections and subsequent innate and adaptive immunity. However, the COPD airway epithelium exhibits an altered antiviral response, leading to enhanced susceptibility to severe disease and impaired IFN signaling. Despite decades of research, there is no effective antiviral therapy for COPD patients. Herein, we review current insights into understanding the mechanisms of viral evasion and host IFN antiviral defense signaling impairment in COPD airway epithelium. Understanding how antiviral mechanisms operate in COPD exacerbations will facilitate the discovery of potential therapeutic interventions to reduce COPD hospitalization and disease severity.

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Somatic cell hemoglobin modulates nitrogen oxide metabolism in the human airway epithelium

Scientific Reports ◽

10.1038/s41598-021-94782-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nadzeya Marozkina ◽

Laura Smith ◽

Yi Zhao ◽

Joe Zein ◽

James F. Chmiel ◽

...

Keyword(s):

Gene Expression ◽

Epithelial Cells ◽

Nitrogen Oxides ◽

Airway Epithelium ◽

Airflow Obstruction ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Human Airway ◽

Human Airway Epithelium ◽

Human Airway Epithelial Cells

AbstractEndothelial hemoglobin (Hb)α regulates endothelial nitric oxide synthase (eNOS) biochemistry. We hypothesized that Hb could also be expressed and biochemically active in the ciliated human airway epithelium. Primary human airway epithelial cells, cultured at air–liquid interface (ALI), were obtained by clinical airway brushings or from explanted lungs. Human airway Hb mRNA data were from publically available databases; or from RT-PCR. Hb proteins were identified by immunoprecipitation, immunoblot, immunohistochemistry, immunofluorescence and liquid chromatography- mass spectrometry. Viral vectors were used to alter Hbβ expression. Heme and nitrogen oxides were measured colorimetrically. Hb mRNA was expressed in human ciliated epithelial cells. Heme proteins (Hbα, β, and δ) were detected in ALI cultures by several methods. Higher levels of airway epithelial Hbβ gene expression were associated with lower FEV1 in asthma. Both Hbβ knockdown and overexpression affected cell morphology. Hbβ and eNOS were apically colocalized. Binding heme with CO decreased extracellular accumulation of nitrogen oxides. Human airway epithelial cells express Hb. Higher levels of Hbβ gene expression were associated with airflow obstruction. Hbβ and eNOS were colocalized in ciliated cells, and heme affected oxidation of the NOS product. Epithelial Hb expression may be relevant to human airways diseases.

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Infection, inflammation and thrombosis: a review of potential mechanisms mediating arterial thrombosis associated with influenza and severe acute respiratory syndrome coronavirus 2

Biological Chemistry ◽

10.1515/hsz-2021-0348 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Stefan Veizades ◽

Alexandria Tso ◽

Patricia K. Nguyen

Keyword(s):

Myocardial Infarction ◽

Severe Acute Respiratory Syndrome ◽

Arterial Thrombosis ◽

Viral Infections ◽

Respiratory Viruses ◽

Causal Connection ◽

Immune Systems ◽

Clinical Observations ◽

Increased Risk ◽

Time Of Infection

Abstract Thrombosis has long been reported as a potentially deadly complication of respiratory viral infections and has recently received much attention during the global coronavirus disease 2019 pandemic. Increased risk of myocardial infarction has been reported during active infections with respiratory viruses, including influenza and severe acute respiratory syndrome coronavirus 2, which persists even after the virus has cleared. These clinical observations suggest an ongoing interaction between these respiratory viruses with the host’s coagulation and immune systems that is initiated at the time of infection but may continue long after the virus has been cleared. In this review, we discuss the epidemiology of viral-associated myocardial infarction, highlight recent clinical studies supporting a causal connection, and detail how the virus’ interaction with the host’s coagulation and immune systems can potentially mediate arterial thrombosis.

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“RESPIRATORY VIRAL INFECTION: AN UNDERRATED ENTITY THAT NEED TO CONSIDER IN MANAGEMENT OF ACUTE EXACERBATION OF COPD”

10.36106/ijar/4700393 ◽

2021 ◽

pp. 6-8

Author(s):

Gyan Singh Meena ◽

Ajith Kumar M S ◽

Shashank Sharma ◽

SP Agnihotri

Keyword(s):

Acute Exacerbation ◽

Viral Infections ◽

Respiratory Viruses ◽

Cross Sectional Study ◽

Viral Etiology ◽

Cross Sectional ◽

Acute Exacerbation Of Copd ◽

Medical College ◽

Copd Patients ◽

Exacerbation Of Copd

BACKGROUND: Acute exacerbation of COPD (AECOPD) is one of the most common cause of hospital admission. It causes signicant morbidity, mortality and inexorable decline in ling function. Many exacerbations are believed to be due to upper and/ lower respiratory tract viral infections, but the incidence of these infections in patients with COPD is still undetermined. Objectives of the study are-(a) To nd out the viral etiology in patients having acute exacerbation of COPD. (b) To correlate the severity of COPD patients having exacerbations with viral etiology. METHODS: This cross-sectional study was carried out on 70 AECOPD patients admitted in department of Respiratory Medicine, Institute of Respiratory Diseases, SMS Medical College, Jaipur during July 2019–June 2020. Demographic and clinical parameters were recorded from each patient during admission. Twin nasopharyngeal/oropharyngeal swabs were collected and are tested for Respiratory viruses via RT-PCR. RESULTS: Respiratory viruses were detected in 15 of 70 (21.42%) patients during exacerbations of COPD. The viruses detected were inuenza (10%), rhinovirus (5.71%), adenovirus (4.29%) and RSV (1.42%). Majority of the patients had exacerbations in severe COPD subgroup, had duration of hospital stay of more than or equal to 5 days, had one episode of acute exacerbation per year and 5, 9, 11 respiratory viruses were detected in this group respectively. CONCLUSION: Viral infections seem to contribute to the exacerbations of COPD in our settings and should be strongly considered in the management of such patients. Considering appropriate antiviral therapy can timely reduce morbidity in an event of an inuenza viral exacerbation.

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EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00368.2013 ◽

2014 ◽

Vol 307 (2) ◽

pp. L186-L196 ◽

Cited By ~ 27

Author(s):

April Kalinowski ◽

Iris Ueki ◽

Gundula Min-Oo ◽

Eric Ballon-Landa ◽

David Knoff ◽

...

Keyword(s):

Epithelial Cells ◽

Viral Infection ◽

Airway Epithelium ◽

Respiratory Virus ◽

Respiratory Viruses ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Egfr Signaling ◽

Respiratory Viral Infection ◽

Egfr Activation

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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Chronic Obstructive Pulmonary Disease Patients Have Increased Levels of Plasma Inflammatory Mediators Reported Upregulated in Severe COVID-19

Frontiers in Immunology ◽

10.3389/fimmu.2021.678661 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nathalie Acevedo ◽

Jose Miguel Escamilla-Gil ◽

Héctor Espinoza ◽

Ronald Regino ◽

Jonathan Ramírez ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Plasma Proteins ◽

Viral Infections ◽

Chronic Obstructive ◽

Healthy Controls ◽

Obstructive Pulmonary Disease ◽

Asthmatic Patients ◽

Copd Patients ◽

Increased Risk

BackgroundChronic obstructive pulmonary disease (COPD) is associated with increased risk of severe COVID-19, but the mechanisms are unclear. Besides, patients with severe COVID-19 have been reported to have increased levels of several immune mediators.MethodsNinety-two proteins were quantified in 315 plasma samples from 118 asthmatics, 99 COPD patients and 98 healthy controls (age 40-90 years), who were recruited in Colombia before the COVID-19 pandemic. Protein levels were compared between each disease group and healthy controls. Significant proteins were compared to the gene signatures of SARS-CoV-2 infection reported in the “COVID-19 Drug and Gene Set Library” and with experimentally tested protein biomarkers of severe COVID-19.ResultsForty-one plasma proteins showed differences between patients and controls. Asthmatic patients have increased levels in IL-6 while COPD patients have a broader systemic inflammatory dysregulation driven by HGF, OPG, and several chemokines (CXCL9, CXCL10, CXCL11, CX3CL1, CXCL1, MCP-3, MCP-4, CCL3, CCL4 and CCL11). These proteins are involved in chemokine signaling pathways related with response to viral infections and some, were found up-regulated upon SARS-CoV-2 experimental infection of Calu-3 cells as reported in the COVID-19 Related Gene Sets database. An increase of HPG, CXCL9, CXCL10, IL-6, MCP-3, TNF and EN-RAGE has also been experimentally detected in patients with severe COVID-19.ConclusionsCOPD patients have altered levels of plasma proteins that have been reported increased in patients with severe COVID-19. Our study suggests that COPD patients have a systemic dysregulation in chemokine networks (including HGF and CXCL9) that could make them more susceptible to severe COVID-19. Also, that IL-6 levels are increased in some asthmatic patients (especially in females) and this may influence their response to COVID-19. The findings in this study depict a novel panel of inflammatory plasma proteins in COPD patients that may potentially associate with increased susceptibility to severe COVID-19 and might be useful as a biomarker signature after future experimental validation.

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A Protective Role of FAM13A in Human Airway Epithelial Cells Upon Exposure to Cigarette Smoke Extract

Frontiers in Physiology ◽

10.3389/fphys.2021.690936 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qing Chen ◽

Maaike de Vries ◽

Kingsley Okechukwu Nwozor ◽

Jacobien A. Noordhoek ◽

Corry-Anke Brandsma ◽

...

Keyword(s):

Epithelial Cells ◽

Cigarette Smoking ◽

Cigarette Smoke ◽

Airway Epithelium ◽

Barrier Function ◽

Cigarette Smoke Extract ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Copd Patients ◽

Epithelial Resistance

BackgroundChronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease characterized by chronic inflammation upon inhalation of noxious particles, e.g., cigarette smoke. FAM13A is one of the genes often found to be associated with COPD, however its function in the pathophysiology of COPD is incompletely understood. We studied its role in airway epithelial barrier integrity and cigarette smoke-induced epithelial responses.Materials and MethodsProtein level and localization of FAM13A was assessed with immunohistochemistry in lung tissue from COPD patients and non-COPD controls. In vitro, FAM13A expression was determined in the absence or presence of cigarette smoke extract (CSE) in primary airway epithelial cells (AECs) from COPD patients and controls by western blotting. FAM13A was overexpressed in cell line 16HBE14o- and its effect on barrier function was monitored real-time by electrical resistance. Expression of junctional protein E-cadherin and β-catenin was assessed by western blotting. The secretion of neutrophil attractant CXCL8 upon CSE exposure was measured by ELISA.ResultsFAM13A was strongly expressed in airway epithelium, but significantly weaker in airways of COPD patients compared to non-COPD controls. In COPD-derived AECs, but not those of controls, FAM13A was significantly downregulated by CSE. 16HBE14o- cells overexpressing FAM13A built up epithelial resistance significantly more rapidly, which was accompanied by higher E-cadherin expression and reduced CSE-induced CXCL8 levels.ConclusionOur data indicate that the expression of FAM13A is lower in airway epithelium of COPD patients compared to non-COPD controls. In addition, cigarette smoking selectively downregulates airway epithelial expression of FAM13A in COPD patients. This may have important consequences for the pathophysiology of COPD, as the more rapid build-up of epithelial resistance upon FAM13A overexpression suggests improved (re)constitution of barrier function. The reduced epithelial secretion of CXCL8 upon CSE-induced damage suggests that lower FAM13A expression upon cigarette smoking may facilitate epithelial-driven neutrophilia.

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Cardiovascular Risk in Patients with COPD: Cardiovascular Comorbidities in Patients with COPD Increase CAT and mMRC Dyspnea Scores

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2021.7942 ◽

2021 ◽

Vol 9 (B) ◽

pp. 1772-1777

Author(s):

Jagoda Stojkovic ◽

Emilija Antova ◽

Dragana Stojkovikj

Keyword(s):

Respiratory Failure ◽

Airflow Obstruction ◽

Forced Expiratory Volume ◽

Severe Exacerbation ◽

Cardiovascular Comorbidity ◽

Versus Group ◽

Group I ◽

Copd Patients ◽

Increased Risk ◽

Group Ii

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a number of different comorbidities. Cardiovascular diseases (CVD) are the most frequent comorbidities in COPD. The economic burden associated with cardiovascular comorbidity (CVC) in this population of patients is considerable. The COPD patients are related to the increased systemic inflammation, reduced capacity for physical activity, and airflow obstruction. AIM: The aim of our investigation was to evaluate the dyspnea as a disabling symptom in COPD patients with cardiovascular comorbidity (CVC) especially heart failure. The main aim of this study is to evaluate its intensity in patients with COPD in stages II according to GOLD. METHODS: The investigation was conducted from December 2019 to January 2020, on pulmonology and allergology clinic and cardiology clinic of medical faculty in Skopje. We investigated 65 outpatients with COPD, 44 with different type of CVD, Group I, and 21 without CVD, Group II. All patients were with partial chronic respiratory failure (In type 1 respiratory failure hypoxemic). Patients, according GOLD initiative, were in COPD stadium II, 70% < forced expiratory volume in 1 s (FEV1)>50%. Heart condition was diagnosed on the basis of clinical examination, electrocardiography, and echocardiography of the heart. Included patients with CVD were with ejection fraction (EF) <65%. Dyspnea was measured with modified MRC (mMRC) dyspnea scale. RESULTS: The forced vital capacity and forced expiratory volume in 1 s were statically significantly higher in Group II with CVD. Dyspnea measured with Modified Medical Research Council (MRC) dyspnea scale showed statistically significantly higher values in Group I COPD patients with CVC (2.9 ± 1.4) versus Group II without CVC (1.7 ± 1.4), (p < 0.05). The perception of the higher dyspnea in Group I was associated with increased COPD assessment test-scores, in Group I: Group I (19.8 ± 9.1) versus Group II: (9.8 ± 9.1), (p < 0.001). The number of exacerbations and what is more important the number of severe exacerbation leading to hospitalizations was statistically higher in patients of Group I with CVC than in Group II without CVC (3.0 ± 1.1 vs. 1.0 ± 2.1), (p < 0.001) and the number of hospitalizations (1.0 ± 1.1 vs. 0.3 ± 2.1) (p < 0.001). CONCLUSION: We can conclude that patients with COPD who have CVC have an increased risk of high symptoms, which mean poor quality of life and increased morbidity.

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Epidemiologic, Experimental, and Clinical Links between Respiratory Syncytial Virus Infection and Asthma

Clinical Microbiology Reviews ◽

10.1128/cmr.00054-07 ◽

2008 ◽

Vol 21 (3) ◽

pp. 495-504 ◽

Cited By ~ 77

Author(s):

Shyam S. Mohapatra ◽

Sandhya Boyapalle

Keyword(s):

Respiratory Syncytial Virus ◽

Childhood Asthma ◽

Molecular Mechanisms ◽

Viral Infections ◽

Severe Disease ◽

Infection Process ◽

Increased Risk ◽

Rsv Infection ◽

Recurrent Wheeze ◽

Syncytial Virus

SUMMARY Virtually all children experience respiratory syncytial virus (RSV) infection at least once during the first 2 years of life, but only a few develop bronchiolitis and more severe disease requiring hospitalization, usually in the first 6 months of life. Children who recover from RSV-induced bronchiolitis are at increased risk for the development of recurrent wheeze and asthma in later childhood. Recent studies suggest that there is an association between RSV-induced bronchiolitis and asthma within the first decade of life but that this association is not significant after age 13. Despite the considerable progress made in our understanding of several aspects of respiratory viral infections, further work needs to be done to clarify the molecular mechanisms of early interactions between virus and host cell and the role of host gene products in the infection process. This review provides a critical appraisal of the literature in epidemiology and experimental research which links RSV infection to asthma. Studies to date demonstrate that there is a significant association between RSV infection and childhood asthma and that preventing severe primary RSV infections can decrease the risk of childhood asthma.

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Host Defense and the Airway Epithelium: Frontline Responses That Protect against Bacterial Invasion and Pneumonia

Journal of Pathogens ◽

10.4061/2011/249802 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 37

Author(s):

Nicholas A. Eisele ◽

Deborah M. Anderson

Keyword(s):

Epithelial Cells ◽

Host Defense ◽

Immune Cells ◽

Airway Epithelium ◽

Inflammatory Cells ◽

Airway Epithelial Cells ◽

Bacterial Invasion ◽

Airway Epithelial ◽

First Line ◽

Protein Matrices

Airway epithelial cells are the first line of defense against invading microbes, and they protect themselves through the production of carbohydrate and protein matrices concentrated with antimicrobial products. In addition, they act as sentinels, expressing pattern recognition receptors that become activated upon sensing bacterial products and stimulate downstream recruitment and activation of immune cells which clear invading microbes. Bacterial pathogens that successfully colonize the lungs must resist these mechanisms or inhibit their production, penetrate the epithelial barrier, and be prepared to resist a barrage of inflammation. Despite the enormous task at hand, relatively few virulence factors coordinate the battle with the epithelium while simultaneously providing resistance to inflammatory cells and causing injury to the lung. Here we review mechanisms whereby airway epithelial cells recognize pathogens and activate a program of antibacterial pathways to prevent colonization of the lung, along with a few examples of how bacteria disrupt these responses to cause pneumonia.

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Human Parechovirus: an Increasingly Recognized Cause of Sepsis-Like Illness in Young Infants

Clinical Microbiology Reviews ◽

10.1128/cmr.00047-17 ◽

2017 ◽

Vol 31 (1) ◽

Cited By ~ 27

Author(s):

Laudi Olijve ◽

Lance Jennings ◽

Tony Walls

Keyword(s):

Viral Infections ◽

Severe Disease ◽

Diagnostic Techniques ◽

Molecular Diagnostic ◽

Molecular Diagnostic Techniques ◽

Human Parechovirus ◽

Content Type ◽

Cns Infections ◽

Young Infants ◽

Increased Risk

SUMMARYHuman parechovirus (HPeV) is increasingly being recognized as a potentially severe viral infection in neonates and young infants. HPeV belongs to the familyPicornaviridaeand is currently divided into 19 genotypes. HPeV-1 is the most prevalent genotype and most commonly causes gastrointestinal and respiratory disease. HPeV-3 is clinically the most important genotype due to its association with severe disease in younger infants, which may partly be explained by its distinct virological properties. In young infants, the typical clinical presentation includes fever, severe irritability, and rash, often leading to descriptions of “hot, red, angry babies.” Infants with severe central nervous system (CNS) infections are at an increased risk of long-term sequelae. Considering the importance of HPeV as a cause of severe viral infections in young infants, we recommend that molecular diagnostic techniques for early detection be included in the standard practice for the investigation of sepsis-like illnesses and CNS infections in this age group.

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