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      Transforming Growth Factor-Beta Promotes Rhinovirus Replication in Bronchial Epithelial Cells by Suppressing the Innate Immune Response

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          Abstract

          Rhinovirus (RV) infection is a major cause of asthma exacerbations which may be due to a deficient innate immune response in the bronchial epithelium. We hypothesized that the pleiotropic cytokine, TGF-β, influences interferon (IFN) production by primary bronchial epithelial cells (PBECs) following RV infection. Exogenous TGF-β 2 increased RV replication and decreased IFN protein secretion in response to RV or double-stranded RNA (dsRNA). Conversely, neutralizing TGF-β antibodies decreased RV replication and increased IFN expression in response to RV or dsRNA. Endogenous TGF-β 2 levels were higher in conditioned media of PBECs from asthmatic donors and the suppressive effect of anti-TGF-β on RV replication was significantly greater in these cells. Basal SMAD-2 activation was reduced when asthmatic PBECs were treated with anti-TGF-β and this was accompanied by suppression of SOCS-1 and SOCS-3 expression. Our results suggest that endogenous TGF-β contributes to a suppressed IFN response to RV infection possibly via SOCS-1 and SOCS-3.

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          Most cited references31

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          Community study of role of viral infections in exacerbations of asthma in 9-11 year old children.

          To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community. Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses. 108 Children aged 9-11 years who had reported wheeze or cough, or both, in a questionnaire. Southampton and surrounding community. Upper and lower respiratory viral infections detected by polymerase chain reaction or conventional methods, reported exacerbations of asthma, computer identified episodes of respiratory tract symptoms or peak flow reductions. Viruses were detected in 80% of reported episodes of reduced peak expiratory flow, 80% of reported episodes of wheeze, and in 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow. The median duration of reported falls in peak expiratory flow was 14 days, and the median maximum fall in peak expiratory flow was 81 l/min. The most commonly identified virus type was rhinovirus. This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children.
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            Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus

            Rhinoviruses are the major trigger of acute asthma exacerbations and asthmatic subjects are more susceptible to these infections. To investigate the underlying mechanisms of this increased susceptibility, we examined virus replication and innate responses to rhinovirus (RV)-16 infection of primary bronchial epithelial cells from asthmatic and healthy control subjects. Viral RNA expression and late virus release into supernatant was increased 50- and 7-fold, respectively in asthmatic cells compared with healthy controls. Virus infection induced late cell lysis in asthmatic cells but not in normal cells. Examination of the early cellular response to infection revealed impairment of virus induced caspase 3/7 activity and of apoptotic responses in the asthmatic cultures. Inhibition of apoptosis in normal cultures resulted in enhanced viral yield, comparable to that seen in infected asthmatic cultures. Examination of early innate immune responses revealed profound impairment of virus-induced interferon-β mRNA expression in asthmatic cultures and they produced >2.5 times less interferon-β protein. In infected asthmatic cells, exogenous interferon-β induced apoptosis and reduced virus replication, demonstrating a causal link between deficient interferon-β, impaired apoptosis and increased virus replication. These data suggest a novel use for type I interferons in the treatment or prevention of virus-induced asthma exacerbations.
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              Making sense of latent TGFbeta activation.

              TGFbeta is secreted as part of a latent complex that is targeted to the extracellular matrix. A variety of molecules, 'TGFbeta activators,' release TGFbeta from its latent state. The unusual temporal discontinuity of TGFbeta synthesis and action and the panoply of TGFbeta effects contribute to the interest in TGF-beta. However, the logical connections between TGFbeta synthesis, storage and action are obscure. We consider the latent TGFbeta complex as an extracellular sensor in which the TGFbeta propeptide functions as the detector, latent-TGFbeta-binding protein (LTBP) functions as the localizer, and TGF-beta functions as the effector. Such a view provides a logical continuity for various aspects of TGFbeta biology and allows us to appreciate TGFbeta biology from a new perspective.
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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, USA )
                1932-6203
                2012
                6 September 2012
                : 7
                : 9
                : e44580
                Affiliations
                [1 ]Academic Unit of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, University Hospital Southampton, Southampton, United Kingdom
                [2 ]National Institute for Health Research, Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, United Kingdom
                [3 ]University of Nottingham, Clinical Sciences Building, Nottingham City Hospital, Nottingham, United Kingdom
                National Jewish Health, United States of America
                Author notes

                Competing Interests: DED and STH are co-founders of Synairgen Research Ltd. and hold shares in Synairgen plc. Synairgen is currently developing inhaled IFN-β for treatment of virus-induced asthma exacerbations. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.

                Conceived and designed the experiments: NB DED STH GJ. Performed the experiments: NB AT GJ. Analyzed the data: NB DED AT GJ. Contributed reagents/materials/analysis tools: GJ. Wrote the paper: NB DED STH GJ PHH. Recruiting normal and asthmatic volunteers: DS BG VK PD. Performing bronchospies: DS BG VK PD. Collecting bronchial brushings: DS BG VK PD.

                Article
                PONE-D-12-01490
                10.1371/journal.pone.0044580
                3435262
                22970254
                af8bda1b-d7ef-4e8a-af74-930a844d274c
                Copyright @ 2012

                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
                : 14 January 2012
                : 9 August 2012
                Page count
                Pages: 13
                Funding
                This work was supported by a Medical Research Council (United Kingdom) Capacity Building Studentship to NB, Medical Research Council grant (G0501506) and the Asthma, Allergy & Inflammation Research Charity. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Immunology
                Immune System
                Cytokines
                Immunity
                Innate Immunity
                Immune Response
                Molecular Cell Biology
                Cellular Types
                Epithelial Cells
                Medicine
                Infectious Diseases
                Viral Diseases
                Common Cold
                Rhinovirus Infection
                Pulmonology
                Asthma

                Uncategorized
                Uncategorized

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