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      Human β-defensin-2 production upon viral and bacterial co-infection is attenuated in COPD

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          Abstract

          Viral-bacterial co-infections are associated with severe exacerbations of COPD. Epithelial antimicrobial peptides, including human β-defensin-2 (HBD-2), are integral to innate host defenses. In this study, we examined how co-infection of airway epithelial cells with rhinovirus and Pseudomonas aeruginosa modulates HBD-2 expression, and whether these responses are attenuated by cigarette smoke and in epithelial cells obtained by bronchial brushings from smokers with normal lung function or from COPD patients. When human airway epithelial cells from normal lungs were infected with rhinovirus, Pseudomonas aeruginosa, or the combination, co-infection with rhinovirus and bacteria resulted in synergistic induction of HBD-2 (p<0.05). The combination of virus and flagellin replicated this synergistic increase (p<0.05), and synergy was not seen using a flagella-deficient mutant Pseudomonas (p<0.05). The effects of Pseudomonas aeruginosa were mediated via interactions of flagellin with TLR5. The effects of HRV-16 depended upon viral replication but did not appear to be mediated via the intracellular RNA helicases, retinoic acid-inducible gene-I or melanoma differentiation-associated gene-5. Cigarette smoke extract significantly decreased HBD-2 production in response to co-infection. Attenuated production was also observed following co-infection of cells obtained from healthy smokers or COPD patients compared to healthy controls (p<0.05). We conclude that co-exposure to HRV-16 and Pseudomonas aeruginosa induces synergistic production of HBD-2 from epithelial cells and that this synergistic induction of HBD-2 is reduced in COPD patients. This may contribute to the more severe exacerbations these patients experience in response to viral-bacterial co-infections.

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          Most cited references26

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          Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary.

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            The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus.

            Inflammasomes are large cytoplasmic complexes that sense microbial infections/danger molecules and induce caspase-1 activation-dependent cytokine production and macrophage inflammatory death. The inflammasome assembled by the NOD-like receptor (NLR) protein NLRC4 responds to bacterial flagellin and a conserved type III secretion system (TTSS) rod component. How the NLRC4 inflammasome detects the two bacterial products and the molecular mechanism of NLRC4 inflammasome activation are not understood. Here we show that NAIP5, a BIR-domain NLR protein required for Legionella pneumophila replication in mouse macrophages, is a universal component of the flagellin-NLRC4 pathway. NAIP5 directly and specifically interacted with flagellin, which determined the inflammasome-stimulation activities of different bacterial flagellins. NAIP5 engagement by flagellin promoted a physical NAIP5-NLRC4 association, rendering full reconstitution of a flagellin-responsive NLRC4 inflammasome in non-macrophage cells. The related NAIP2 functioned analogously to NAIP5, serving as a specific inflammasome receptor for TTSS rod proteins such as Salmonella PrgJ and Burkholderia BsaK. Genetic analysis of Chromobacterium violaceum infection revealed that the TTSS needle protein CprI can stimulate NLRC4 inflammasome activation in human macrophages. Similarly, CprI is specifically recognized by human NAIP, the sole NAIP family member in human. The finding that NAIP proteins are inflammasome receptors for bacterial flagellin and TTSS apparatus components further predicts that the remaining NAIP family members may recognize other unidentified microbial products to activate NLRC4 inflammasome-mediated innate immunity. © 2011 Macmillan Publishers Limited. All rights reserved
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              Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease.

              The effects of respiratory viral infection on the time course of chronic obstructive pulmonary disease (COPD) exacerbation were examined by monitoring changes in systemic inflammatory markers in stable COPD and at exacerbation. Eighty-three patients with COPD (mean [SD] age, 66.6 [7.1] yr, FEV(1), 1.06 [0.61] L) recorded daily peak expiratory flow rate and any increases in respiratory symptoms. Nasal samples and blood were taken for respiratory virus detection by culture, polymerase chain reaction, and serology, and plasma fibrinogen and serum interleukin-6 (IL-6) were determined at stable baseline and exacerbation. Sixty-four percent of exacerbations were associated with a cold occurring up to 18 d before exacerbation. Seventy-seven viruses (39 [58.2%] rhinoviruses) were detected in 66 (39.2%) of 168 COPD exacerbations in 53 (64%) patients. Viral exacerbations were associated with frequent exacerbators, colds with increased dyspnea, a higher total symptom count at presentation, a longer median symptom recovery period of 13 d, and a tendency toward higher plasma fibrinogen and serum IL-6 levels. Non-respiratory syncytial virus (RSV) respiratory viruses were detected in 11 (16%), and RSV in 16 (23.5%), of 68 stable COPD patients, with RSV detection associated with higher inflammatory marker levels. Respiratory virus infections are associated with more severe and frequent exacerbations, and may cause chronic infection in COPD. Prevention and early treatment of viral infections may lead to a decreased exacerbation frequency and morbidity associated with COPD.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 May 2017
                2017
                : 12
                : 5
                : e0175963
                Affiliations
                [1 ]Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
                [2 ]Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
                [3 ]Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
                University of Alabama at Birmingham, UNITED STATES
                Author notes

                Competing Interests: DP has received consulting fees from AstraZeneca, Janssen, Pfizer and Procter & Gamble, and has received research grants from AstraZeneca and MedImmune. None of these applied to the current work. RL has received consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Janssen, and has received Research Grants from AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, Roche, Sanofi Aventis and Amgen. None of these applied to the current work. All other authors have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                • Conceptualization: JWA CK WSL DP RL.

                • Data curation: JWA DP RL.

                • Formal analysis: JWA JCM DP RL.

                • Funding acquisition: DP RL.

                • Investigation: JWA JCM SW SLT CK CS BM CJD.

                • Methodology: JWA BM CK DP RL.

                • Project administration: DP RL.

                • Resources: CK SW SLT CJD WSL DP RL.

                • Supervision: DP RL.

                • Validation: DP RL.

                • Visualization: JWA DP RL.

                • Writing – original draft: JWA DP RL.

                • Writing – review & editing: JWA JCM CK SW SLT CS BM CJD WSL DP RL.

                Article
                PONE-D-16-43188
                10.1371/journal.pone.0175963
                5425185
                28489911
                04c72541-4b6d-4070-9c21-eeb0b19449b1
                © 2017 Arnason et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 October 2016
                : 3 April 2017
                Page count
                Figures: 9, Tables: 1, Pages: 19
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: 82049
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: 43923
                Award Recipient :
                Grant numbers 82049 (to RL) & 43923 (to DP) from the Canadian Institutes of Health Research (CIHR) supported this work. Dr. Leigh holds the GlaxoSmithKline-CIHR Professorship in Inflammatory Lung Diseases at the University of Calgary and Dr. Proud is the recipient of a Tier 1 Canada Research Chair in Inflammatory Airway Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Infectious Diseases
                Co-Infections
                Medicine and Health Sciences
                Pulmonology
                Chronic Obstructive Pulmonary Disease
                Biology and Life Sciences
                Immunology
                Immune System Proteins
                Immune Receptors
                Toll-like Receptors
                Medicine and Health Sciences
                Immunology
                Immune System Proteins
                Immune Receptors
                Toll-like Receptors
                Biology and Life Sciences
                Biochemistry
                Proteins
                Immune System Proteins
                Immune Receptors
                Toll-like Receptors
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Immune Receptors
                Toll-like Receptors
                Biology and life sciences
                Genetics
                Gene expression
                Gene regulation
                Small interfering RNAs
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                Non-coding RNA
                Small interfering RNAs
                Biology and Life Sciences
                Microbiology
                Bacteriology
                Bacterial Physiology
                Flagellin
                Biology and Life Sciences
                Microbiology
                Microbial Physiology
                Bacterial Physiology
                Flagellin
                Biology and Life Sciences
                Biochemistry
                Proteins
                Flagellin
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Epithelial Cells
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Pseudomonas Aeruginosa
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Bacterial Pathogens
                Pseudomonas Aeruginosa
                Biology and Life Sciences
                Organisms
                Bacteria
                Pseudomonas
                Pseudomonas Aeruginosa
                Medicine and Health Sciences
                Infectious Diseases
                Viral Diseases
                Rhinovirus Infection
                Custom metadata
                All relevant data are presented within the paper. In addition, the study's raw, minimal data set has been uploaded in a Supporting Information file.

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