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Sebastian L Johnston - One of the best experts on this subject based on the ideXlab platform.

  • inhaled dsrna and Rhinovirus evoke neutrophilic exacerbation and lung expression of thymic stromal lymphopoietin in allergic mice with established experimental asthma
    Allergy, 2014
    Co-Authors: I Mahmutovicpersson, Nicholas Glanville, Nathan W. Bartlett, Sebastian L Johnston, Hamid Akbarshahi, Angelica Brandelius, Lena Uller
    Abstract:

    Rhinovirus Infection or dsRNA stimulation increased thymic stromal lymphopoietin (TSLP), an upstream pro-allergic cytokine, in asthmatic bronchial epithelial cells. We hypothesized that dsRNA challenges superimposed on established experimental allergic asthma constitute a useful exacerbation model. We further hypothesized that TSLP is induced at dsRNA- and rhinoviral Infection-induced exacerbations.

  • evaluation of coagulation activation after Rhinovirus Infection in patients with asthma and healthy control subjects an observational study
    Respiratory Research, 2014
    Co-Authors: Christof J Majoor, Sebastian L Johnston, Marianne A Van De Pol, Pieter Willem Kamphuisen, Joost C M Meijers, Richard Molenkamp, Katja C Wolthers, Tom Van Der Poll, Rienk Nieuwland, Peter J Sterk
    Abstract:

    Asthma exacerbations are frequently triggered by Rhinovirus Infections. Both asthma and respiratory tract Infection can activate haemostasis. Therefore we hypothesized that experimental Rhinovirus-16 Infection and asthmatic airway inflammation act in synergy on the haemostatic balance. 28 patients (14 patients with mild allergic asthma and 14 healthy non-allergic controls) were infected with low-dose Rhinovirus type 16. Venous plasma and bronchoalveolar lavage fluid (BAL fluid) were obtained before and 6 days after Infection to evaluate markers of coagulation activation, thrombin-antithrombin complexes, von Willebrand factor, plasmin-antiplasmin complexes, plasminogen activator inhibitor type-1, endogenous thrombin potential and tissue factor-exposing microparticles by fibrin generation test, in plasma and/or BAL fluid. Data were analysed by nonparametric tests (Wilcoxon, Mann Whitney and Spearman correlation). 13 patients with mild asthma (6 females, 19-29 y) and 11 healthy controls (10 females, 19-31 y) had a documented Rhinovirus-16 Infection. Rhinovirus-16 challenge resulted in a shortening of the fibrin generation test in BAL fluid of asthma patients (t = -1: 706 s vs. t = 6: 498 s; p = 0.02), but not of controls (t = -1: 693 s vs. t = 6: 636 s; p = 0.65). The fold change in tissue factor-exposing microparticles in BAL fluid inversely correlated with the fold changes in eosinophil cationic protein and myeloperoxidase in BAL fluid after virus Infection (r = -0.517 and -0.528 resp., both p = 0.01). Rhinovirus-16 challenge led to increased plasminogen activator inhibitor type-1 levels in plasma in patients with asthma (26.0 ng/mL vs. 11.5 ng/mL in healthy controls, p = 0.04). Rhinovirus-16 load in BAL showed a linear correlation with the fold change in endogenous thrombin potential, plasmin-antiplasmin complexes and plasminogen activator inhibitor type-1. Experimental Rhinovirus Infection induces procoagulant changes in the airways of patients with asthma through increased activity of tissue factor-exposing microparticles. These microparticle-associated procoagulant changes are associated with both neutrophilic and eosinophilic inflammation. Systemic activation of haemostasis increases with Rhinoviral load. This trial was registered at the Dutch trial registry ( http://www.trialregister.nl ): NTR1677 .

  • experimental Rhinovirus Infection in copd implications for antiviral therapies
    Antiviral Research, 2014
    Co-Authors: Natasha C Gunawardana, Sebastian L Johnston, Lydia J Finney, Patrick Mallia
    Abstract:

    Chronic obstructive pulmonary disease (COPD) is a major public health problem and will be one of the leading global causes of mortality over the coming decades. Much of the morbidity, mortality and health care costs of COPD are attributable to acute exacerbations, the commonest causes of which are respiratory Infections. Respiratory viruses are frequently detected in COPD exacerbations but direct proof of a causative relationship has been lacking. We have developed a model of COPD exacerbation using experimental Rhinovirus Infection in COPD patients and this has established a causative relationship between virus Infection and exacerbations. In addition it has determined some of the molecular mechanisms linking virus Infections to COPD exacerbations and identified potential new therapeutic targets. This new data should stimulate research into the role of antiviral agents as potential treatments for COPD exacerbations. Testing of antiviral agents has been hampered by the lack of a small animal model for Rhinovirus Infection and experimental Rhinovirus Infection in healthy volunteers has been used to test treatments for the common cold. Experimental Rhinovirus Infection in COPD subjects offers the prospect of a model that can be used to evaluate the effects of new treatments for virus-induced COPD exacerbations, and provide essential data that can be used in making decisions regarding large scale clinical trials.

  • systemic tryptophan and kynurenine catabolite levels relate to severity of Rhinovirus induced asthma exacerbation a prospective study with a parallel group design
    Thorax, 2013
    Co-Authors: Koenraad F Van Der Sluijs, Marianne A Van De Pol, Richard Molenkamp, Katja C Wolthers, Wim Kulik, Annemiek Dijkhuis, Barbara Smids, Hetty Van Eijk, Jos A Karlas, Sebastian L Johnston
    Abstract:

    Background Patients with allergic asthma have exacerbations which are frequently caused by Rhinovirus Infection. The antiviral tryptophan-catabolising enzyme indoleamine 2,3-dioxygenase (IDO) is induced by interferon-γ and suppressed by Th2 mediators interleukin (IL)-4 and IL-13. We hypothesised that local IDO activity after viral airway Infection is lower in patients with allergic asthma than in healthy controls. Objective To determine whether IDO activity differs between patients with allergic asthma and healthy individuals before and after Rhinovirus Infection. Methods Healthy individuals and patients with allergic asthma were experimentally infected with low-dose (10 TCID50) Rhinovirus 16. Blood, bronchoalveolar lavage fluid and exhaled breath condensate (for mass spectrometry by UPLC-MS/MS) were obtained before and after Rhinovirus challenge. Results IDO activity was not induced by Rhinovirus Infection in either group, despite increases in cold scores. However, baseline pulmonary IDO activity was lower in patients with allergic asthma than in healthy individuals. In contrast, systemic tryptophan and its catabolites were markedly higher in patients with allergic asthma. Moreover, systemic quinolinic acid and tryptophan were associated with eosinophil cationic protein (r=0.43 and r=0.78, respectively) and eosinophils (r=0.38 and r=0.58, respectively) in bronchoalveolar lavage fluid and peak asthma symptom scores after Rhinovirus challenge (r=0.53 and r=0.64, respectively). Conclusions Rhinovirus Infection by itself induces no IDO activity, but the reduced pulmonary IDO activity in patients with allergic asthma at baseline may underlie a reduced control of viral Infections. Notably, the enhanced systemic catabolism of tryptophan in patients with allergic asthma was strongly related to the outcome of Rhinovirus challenge in asthma and may serve as a prognostic factor.

  • Rhinovirus Infection causes steroid resistance in airway epithelium through nuclear factor κb and c jun n terminal kinase activation
    The Journal of Allergy and Clinical Immunology, 2013
    Co-Authors: Alberto Papi, Marco Contoli, Luminita A Stanciu, Ian M Adcock, Cinzia M Bellettato, Anna Padovani, Paolo Casolari, Peter J Barnes, Sebastian L Johnston
    Abstract:

    Background Although inhaled glucocorticoids are the mainstays of asthma treatment, they are poorly effective at treating and preventing virus-induced asthma exacerbations. The major viruses precipitating asthma exacerbations are Rhinoviruses. Objective We sought to evaluate whether Rhinovirus Infection interferes with the mechanisms of action of glucocorticoids. Methods Cultured primary human bronchial or transformed (A549) respiratory epithelial cells were infected with Rhinovirus 16 (RV-16) before dexamethasone exposure. Glucocorticoid receptor (GR) α nuclear translocation, glucocorticoid response element (GRE) binding, and transactivation/transrepression functional readouts were evaluated by using immunocytochemistry, Western blotting, DNA binding assays, real-time quantitative PCR, coimmunoprecipitation, and ELISA techniques. Specific inhibitors of c-Jun N-terminal kinase (JNK) and of IκB kinase (IKK) were used to investigate the involvement of intracellular signaling pathways. Results RV-16 Infection impaired dexamethasone-dependent (1) inhibition of IL-1β–induced CXCL8 release, (2) induction of mitogen-activated protein kinase phosphatase 1 gene expression, and (3) binding of GR to GREs in airway epithelial cells. This was associated with impaired GRα nuclear translocation, as assessed by means of both immunochemistry (54.0% ± 6.8% vs 24.7% ± 3.8% GR-positive nuclei after 10 nmol/L dexamethasone treatment in sham- or RV-16–infected cells, respectively; P Conclusion RV-16 Infection of human airway epithelium induces glucocorticoid resistance. Inhibition of RV-16–induced JNK and nuclear factor κB activation fully reversed Rhinovirus impairment of both GRα nuclear translocation and the transactivation/transrepression activities of glucocorticoids.

Patrick Mallia - One of the best experts on this subject based on the ideXlab platform.

  • human Rhinovirus Infection and copd role in exacerbations and potential for therapeutic targets
    Expert Review of Respiratory Medicine, 2020
    Co-Authors: John Cafferkey, Patrick Mallia, James Coultas
    Abstract:

    Respiratory virus Infections (predominantly Rhinoviruses) are the commonly identified in COPD exacerbations but debate about their role as a trigger of exacerbations continues. Experimental infecti...

  • bronchial mucosal ifn α β and pattern recognition receptor expression in patients with experimental Rhinovirus induced asthma exacerbations
    The Journal of Allergy and Clinical Immunology, 2019
    Co-Authors: Jie Zhu, Simon D Message, Tatiana Kebadze, Marco Contoli, Patrick Mallia, Christine K Ward
    Abstract:

    Background The innate immune system senses viral Infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in Rhinovirus-induced asthma exacerbations in vivo are uncertain. Objectives We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after Rhinovirus Infection in atopic asthmatic patients and control subjects. Methods Immunohistochemistry was used to detect expression of IFN-α, IFN-β, and the PRRs: Toll-like receptor 3, melanoma differentiation–associated gene 5, and retinoic acid–inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after Rhinovirus Infection. Results We observed IFN-α/β deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-α/β expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during Rhinovirus Infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/β in asthmatic patients during Infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during Rhinovirus Infection. Rhinovirus Infection–increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. Conclusions Bronchial epithelial IFN-α/β expression and numbers of subepithelial IFN-α/β–expressing monocytes/macrophages during Infection were both deficient in asthmatic patients. Lower epithelial IFN-α/β expression was associated with adverse clinical outcomes after Rhinovirus Infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during Infection were also related to greater viral load/illness severity.

  • il 15 complexes induce nk and t cell responses independent of type i ifn signaling during Rhinovirus Infection
    Mucosal Immunology, 2014
    Co-Authors: Annabelle Jayaraman, Simon D Message, Julia Aniscenko, Betty Shamji, Patrick Mallia, Gaetano Caramori, Alberto Papi, David A Jackson, Rebecca M Pearson, Matthew J Edwards
    Abstract:

    Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during Rhinovirus Infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Rα, which in turn were required for NK- and CD8(+) T-cell responses. Treatment with IL-15-IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9, and CXCL10 followed by recruitment of activated, IFN-γ-expressing NK, CD8(+), and CD4(+) T cells. Treating infected IFNAR1(-/-) mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8(+)-, and CD4(+)-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.

  • airway inflammation and illness severity in response to experimental Rhinovirus Infection in asthma
    Chest, 2014
    Co-Authors: Simon D Message, Tatiana Kebadze, Marco Contoli, Patrick Mallia, Alberto Papi, Christine K Ward, Elliot S Barnathan, Mary Ann Mascelli, Luminita A Stanciu
    Abstract:

    Background: The nature of bronchial mucosal infl ammation and its physiologic and clinical significance in Rhinovirus-induced asthma exacerbations is unclear. We investigated bronchial mucosal infl ammatory response and its association with physiologic and clinical outcomes in an experimental model of Rhinovirus-induced asthma exacerbations. Methods: We used immunohistochemistry methods to detect phenotypes of infl ammatory cells infi ltrating the bronchial mucosa before and after experimental Rhinovirus Infection in 10 subjects with asthma and 15 normal subjects. Results: Compared with baseline, Rhinovirus Infection signifi cantly increased the number of epithelial ( P 5 .005) and subepithelial ( P 5 .017) neutrophils in subjects with asthma only and subepithelial CD68 1 macrophages in both subjects with asthma ( P 5 .009) and normal subjects ( P 5 .018) but more so in those with asthma ( P 5 .021). Numbers of CD45 1 , CD68 1 , and CD20 1 cells; neutrophils; and eosinophils at day 4 postInfection were positively associated with virus load ( r 5 0.50-0.72, P 5 .016-0.03). At acute Infection in subjects with asthma, CD4 1 cells correlated with chest symptom scores ( r 5 0.69, P 5 .029), the fall in the 10% fall in FEV 1 (PC 10 ) correlated with neutrophils ( r 5 2 0.89, P 5 .029), the PC 10 correlated inversely with CD4 1 ( r 5 2 0.67, P 5 .023) and CD8 1 cells ( r 5 2 0.65, P 5 .03), the 20% fall in FEV 1 was inversely associated with CD20 1 cells ( r 5 2 0.65, P 5 .03), and higher epithelial CD8 1 cell counts were signifi cantly associated with a greater maximum fall in FEV 1 ( r 5 2 0.72, P 5 .03), whereas higher subepithelial mast cell counts were signifi cantly associated with a lower maximum percent fall in peak expiratory fl ow ( r 5 0.8, P 5 .024). Conclusions: In subjects with asthma, Rhinovirus Infection induces bronchial mucosal neutrophilia and more severe monocyte/macrophage infi ltration than in normal subjects. Airway neutrophils, eosinophils, and T and B lymphocytes during Infection are related to virus load and physiologic and clinical severity, whereas mast cells are related to greater lung function. CHEST 2014; 145(6):1219 –1229 Abbreviations: PC 10 5 10% fall in FEV 1 ; PEF 5 peak expiratory fl ow; RV 5 Rhinovirus

  • experimental Rhinovirus Infection in copd implications for antiviral therapies
    Antiviral Research, 2014
    Co-Authors: Natasha C Gunawardana, Sebastian L Johnston, Lydia J Finney, Patrick Mallia
    Abstract:

    Chronic obstructive pulmonary disease (COPD) is a major public health problem and will be one of the leading global causes of mortality over the coming decades. Much of the morbidity, mortality and health care costs of COPD are attributable to acute exacerbations, the commonest causes of which are respiratory Infections. Respiratory viruses are frequently detected in COPD exacerbations but direct proof of a causative relationship has been lacking. We have developed a model of COPD exacerbation using experimental Rhinovirus Infection in COPD patients and this has established a causative relationship between virus Infection and exacerbations. In addition it has determined some of the molecular mechanisms linking virus Infections to COPD exacerbations and identified potential new therapeutic targets. This new data should stimulate research into the role of antiviral agents as potential treatments for COPD exacerbations. Testing of antiviral agents has been hampered by the lack of a small animal model for Rhinovirus Infection and experimental Rhinovirus Infection in healthy volunteers has been used to test treatments for the common cold. Experimental Rhinovirus Infection in COPD subjects offers the prospect of a model that can be used to evaluate the effects of new treatments for virus-induced COPD exacerbations, and provide essential data that can be used in making decisions regarding large scale clinical trials.

Simon D Message - One of the best experts on this subject based on the ideXlab platform.

  • experimental Rhinovirus Infection induces an antiviral response in circulating b cells which is dysregulated in patients with asthma
    Allergy, 2021
    Co-Authors: Oliver F Wirz, Kirstin Jansen, Pattraporn Satitsuksanoa, Willem Van De Veen, Ge Tan, Milena Sokolowska, David Mirer, Barbara Stanic, Simon D Message
    Abstract:

    BACKGROUND Rhinoviruses are the predominant cause of respiratory viral Infections and are strongly associated with asthma exacerbations. While humoral immunity plays an important role during virus Infections, cellular aspects of this response are less well understood. Here, we investigated the antiviral response of circulating B cells upon experimental Rhinovirus Infection in healthy individuals and asthma patients. METHODS We purified B cells from experimentally infected healthy individuals and patients with asthma and subjected them to total RNA-sequencing. Rhinovirus-derived RNA was measured in isolated B cells using a highly sensitive PCR. B cells were stimulated with Rhinovirus in vitro to further study gene expression, expression of antiviral proteins and B-cell differentiation in response Rhinovirus stimulation. Protein expression of pro-inflammatory cytokines in response to Rhinovirus was assessed using a proximity extension assay. RESULTS B cells isolated from experimentally infected subjects exhibited an antiviral gene profile linked to IFN-alpha, carried viral RNA in vivo and were transiently infected by Rhinovirus in vitro. B cells rapidly differentiated into plasmablasts upon Rhinovirus stimulation. While B cells lacked expression of interferons in response to Rhinovirus exposure, co-stimulation with Rhinovirus and IFN-alpha upregulated pro-inflammatory cytokine expression suggesting a potential new function of B cells during virus Infections. Asthma patients showed extensive upregulation and dysregulation of antiviral gene expression. CONCLUSION These findings add to the understanding of systemic effects of Rhinovirus Infections on B-cell responses in the periphery, show potential dysregulation in patients with asthma and might also have implications during Infection with other respiratory viruses.

  • loss of regulatory capacity in t regulatory cells upon Rhinovirus Infection
    The Journal of Allergy and Clinical Immunology, 2021
    Co-Authors: Kirstin Jansen, Simon D Message, Oliver F Wirz, Pattraporn Satitsuksanoa, Willem Van De Veen, Ge Tan, Milena Sokolowska, David Mirer, Tatiana Kebadze
    Abstract:

    Background Respiratory Infections with Rhinoviruses (RV) are strongly associated with development and exacerbations of asthma, and they pose an additional health risk for subjects with allergy. Objective How RV Infections and chronic allergic diseases are linked and what role RV plays in the breaking of tolerance in regulatory T (Treg) cells is unknown. Therefore, this study aims to investigate the effects of RV on Treg cells. Methods Treg cells were isolated from subjects with asthma and controls after experimental Infection with the RV-A16 (RV16) and analyzed with next-generation sequencing. Additionally, suppression assays, quantitative PCR assays, and protein quantifications were performed with Treg cells after in vitro RV16 Infection. Results RV16 induced a strong antiviral response in Treg cells from subjects with asthma and controls, including the upregulation of IFI44L, MX1, ISG15, IRF7, and STAT1. In subjects with asthma, the inflammatory response was exaggerated and showed a dysregulated immune response compared with that in the controls. Furthermore, subjects with asthma failed to upregulate several immunosuppressive molecules such as CTLA4 and CD69, and they upregulated the inflammasome-related genes PYCARD and AIM2. Additionally, RV16 reduced the suppressive capacity of Treg cells from healthy subjects and subjects with asthma in vitro and increased TH2 cell–type cytokine production. Conclusions Treg cells from healthy subjects and subjects with asthma displayed an antiviral response after RV Infection and showed reduced suppressive capacity. These data suggest that Treg cell function might be altered or impaired during RV Infections, which might play an important role in the association between RV and the development of asthma and asthma exacerbations.

  • bronchial mucosal ifn α β and pattern recognition receptor expression in patients with experimental Rhinovirus induced asthma exacerbations
    The Journal of Allergy and Clinical Immunology, 2019
    Co-Authors: Jie Zhu, Simon D Message, Tatiana Kebadze, Marco Contoli, Patrick Mallia, Christine K Ward
    Abstract:

    Background The innate immune system senses viral Infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in Rhinovirus-induced asthma exacerbations in vivo are uncertain. Objectives We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after Rhinovirus Infection in atopic asthmatic patients and control subjects. Methods Immunohistochemistry was used to detect expression of IFN-α, IFN-β, and the PRRs: Toll-like receptor 3, melanoma differentiation–associated gene 5, and retinoic acid–inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after Rhinovirus Infection. Results We observed IFN-α/β deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-α/β expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during Rhinovirus Infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/β in asthmatic patients during Infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during Rhinovirus Infection. Rhinovirus Infection–increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. Conclusions Bronchial epithelial IFN-α/β expression and numbers of subepithelial IFN-α/β–expressing monocytes/macrophages during Infection were both deficient in asthmatic patients. Lower epithelial IFN-α/β expression was associated with adverse clinical outcomes after Rhinovirus Infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during Infection were also related to greater viral load/illness severity.

  • il 15 complexes induce nk and t cell responses independent of type i ifn signaling during Rhinovirus Infection
    Mucosal Immunology, 2014
    Co-Authors: Annabelle Jayaraman, Simon D Message, Julia Aniscenko, Betty Shamji, Patrick Mallia, Gaetano Caramori, Alberto Papi, David A Jackson, Rebecca M Pearson, Matthew J Edwards
    Abstract:

    Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during Rhinovirus Infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Rα, which in turn were required for NK- and CD8(+) T-cell responses. Treatment with IL-15-IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9, and CXCL10 followed by recruitment of activated, IFN-γ-expressing NK, CD8(+), and CD4(+) T cells. Treating infected IFNAR1(-/-) mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8(+)-, and CD4(+)-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.

  • airway inflammation and illness severity in response to experimental Rhinovirus Infection in asthma
    Chest, 2014
    Co-Authors: Simon D Message, Tatiana Kebadze, Marco Contoli, Patrick Mallia, Alberto Papi, Christine K Ward, Elliot S Barnathan, Mary Ann Mascelli, Luminita A Stanciu
    Abstract:

    Background: The nature of bronchial mucosal infl ammation and its physiologic and clinical significance in Rhinovirus-induced asthma exacerbations is unclear. We investigated bronchial mucosal infl ammatory response and its association with physiologic and clinical outcomes in an experimental model of Rhinovirus-induced asthma exacerbations. Methods: We used immunohistochemistry methods to detect phenotypes of infl ammatory cells infi ltrating the bronchial mucosa before and after experimental Rhinovirus Infection in 10 subjects with asthma and 15 normal subjects. Results: Compared with baseline, Rhinovirus Infection signifi cantly increased the number of epithelial ( P 5 .005) and subepithelial ( P 5 .017) neutrophils in subjects with asthma only and subepithelial CD68 1 macrophages in both subjects with asthma ( P 5 .009) and normal subjects ( P 5 .018) but more so in those with asthma ( P 5 .021). Numbers of CD45 1 , CD68 1 , and CD20 1 cells; neutrophils; and eosinophils at day 4 postInfection were positively associated with virus load ( r 5 0.50-0.72, P 5 .016-0.03). At acute Infection in subjects with asthma, CD4 1 cells correlated with chest symptom scores ( r 5 0.69, P 5 .029), the fall in the 10% fall in FEV 1 (PC 10 ) correlated with neutrophils ( r 5 2 0.89, P 5 .029), the PC 10 correlated inversely with CD4 1 ( r 5 2 0.67, P 5 .023) and CD8 1 cells ( r 5 2 0.65, P 5 .03), the 20% fall in FEV 1 was inversely associated with CD20 1 cells ( r 5 2 0.65, P 5 .03), and higher epithelial CD8 1 cell counts were signifi cantly associated with a greater maximum fall in FEV 1 ( r 5 2 0.72, P 5 .03), whereas higher subepithelial mast cell counts were signifi cantly associated with a lower maximum percent fall in peak expiratory fl ow ( r 5 0.8, P 5 .024). Conclusions: In subjects with asthma, Rhinovirus Infection induces bronchial mucosal neutrophilia and more severe monocyte/macrophage infi ltration than in normal subjects. Airway neutrophils, eosinophils, and T and B lymphocytes during Infection are related to virus load and physiologic and clinical severity, whereas mast cells are related to greater lung function. CHEST 2014; 145(6):1219 –1229 Abbreviations: PC 10 5 10% fall in FEV 1 ; PEF 5 peak expiratory fl ow; RV 5 Rhinovirus

Marco Contoli - One of the best experts on this subject based on the ideXlab platform.

  • bronchial mucosal ifn α β and pattern recognition receptor expression in patients with experimental Rhinovirus induced asthma exacerbations
    The Journal of Allergy and Clinical Immunology, 2019
    Co-Authors: Jie Zhu, Simon D Message, Tatiana Kebadze, Marco Contoli, Patrick Mallia, Christine K Ward
    Abstract:

    Background The innate immune system senses viral Infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in Rhinovirus-induced asthma exacerbations in vivo are uncertain. Objectives We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after Rhinovirus Infection in atopic asthmatic patients and control subjects. Methods Immunohistochemistry was used to detect expression of IFN-α, IFN-β, and the PRRs: Toll-like receptor 3, melanoma differentiation–associated gene 5, and retinoic acid–inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after Rhinovirus Infection. Results We observed IFN-α/β deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-α/β expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during Rhinovirus Infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/β in asthmatic patients during Infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during Rhinovirus Infection. Rhinovirus Infection–increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. Conclusions Bronchial epithelial IFN-α/β expression and numbers of subepithelial IFN-α/β–expressing monocytes/macrophages during Infection were both deficient in asthmatic patients. Lower epithelial IFN-α/β expression was associated with adverse clinical outcomes after Rhinovirus Infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during Infection were also related to greater viral load/illness severity.

  • airway inflammation and illness severity in response to experimental Rhinovirus Infection in asthma
    Chest, 2014
    Co-Authors: Simon D Message, Tatiana Kebadze, Marco Contoli, Patrick Mallia, Alberto Papi, Christine K Ward, Elliot S Barnathan, Mary Ann Mascelli, Luminita A Stanciu
    Abstract:

    Background: The nature of bronchial mucosal infl ammation and its physiologic and clinical significance in Rhinovirus-induced asthma exacerbations is unclear. We investigated bronchial mucosal infl ammatory response and its association with physiologic and clinical outcomes in an experimental model of Rhinovirus-induced asthma exacerbations. Methods: We used immunohistochemistry methods to detect phenotypes of infl ammatory cells infi ltrating the bronchial mucosa before and after experimental Rhinovirus Infection in 10 subjects with asthma and 15 normal subjects. Results: Compared with baseline, Rhinovirus Infection signifi cantly increased the number of epithelial ( P 5 .005) and subepithelial ( P 5 .017) neutrophils in subjects with asthma only and subepithelial CD68 1 macrophages in both subjects with asthma ( P 5 .009) and normal subjects ( P 5 .018) but more so in those with asthma ( P 5 .021). Numbers of CD45 1 , CD68 1 , and CD20 1 cells; neutrophils; and eosinophils at day 4 postInfection were positively associated with virus load ( r 5 0.50-0.72, P 5 .016-0.03). At acute Infection in subjects with asthma, CD4 1 cells correlated with chest symptom scores ( r 5 0.69, P 5 .029), the fall in the 10% fall in FEV 1 (PC 10 ) correlated with neutrophils ( r 5 2 0.89, P 5 .029), the PC 10 correlated inversely with CD4 1 ( r 5 2 0.67, P 5 .023) and CD8 1 cells ( r 5 2 0.65, P 5 .03), the 20% fall in FEV 1 was inversely associated with CD20 1 cells ( r 5 2 0.65, P 5 .03), and higher epithelial CD8 1 cell counts were signifi cantly associated with a greater maximum fall in FEV 1 ( r 5 2 0.72, P 5 .03), whereas higher subepithelial mast cell counts were signifi cantly associated with a lower maximum percent fall in peak expiratory fl ow ( r 5 0.8, P 5 .024). Conclusions: In subjects with asthma, Rhinovirus Infection induces bronchial mucosal neutrophilia and more severe monocyte/macrophage infi ltration than in normal subjects. Airway neutrophils, eosinophils, and T and B lymphocytes during Infection are related to virus load and physiologic and clinical severity, whereas mast cells are related to greater lung function. CHEST 2014; 145(6):1219 –1229 Abbreviations: PC 10 5 10% fall in FEV 1 ; PEF 5 peak expiratory fl ow; RV 5 Rhinovirus

  • lymphocyte subsets in experimental Rhinovirus Infection in chronic obstructive pulmonary disease
    Respiratory Medicine, 2014
    Co-Authors: Simon D Message, Katrina Gray, Aurica G Telcian, Marco Contoli, Patrick Mallia, Vasile Lazastanca
    Abstract:

    Summary Background: COPD is associated with increased numbers of T cells in the lungs, particularly CD8þ T cells. The mechanisms of increased T cells are unknown but may be related to repeated virus Infections in COPD patients. We analysed lymphocyte subsets in blood and bronchoalveolar lavage in smokers and COPD subjects during experimental Rhinovirus Infections. Methods: Lymphocytes were isolated from blood and bronchoalveolar lavage from COPD subjects and non-obstructed smokers prior to, and following experimental Rhinovirus Infection. Lymphocyte surface markers and intracellular cytokines were analysed using flow cytometry. Results: Following Rhinovirus Infection CD4þ and CD8þ T cell numbers in the COPD subjects were significantly reduced in blood and CD3þ and CD8þ T cells increased in bronchoalveolar lavage compared to baseline. T cells did not increase in BAL in the control subjects. CD3þ T cells correlated with virus load.

  • Rhinovirus Infection causes steroid resistance in airway epithelium through nuclear factor κb and c jun n terminal kinase activation
    The Journal of Allergy and Clinical Immunology, 2013
    Co-Authors: Alberto Papi, Marco Contoli, Luminita A Stanciu, Ian M Adcock, Cinzia M Bellettato, Anna Padovani, Paolo Casolari, Peter J Barnes, Sebastian L Johnston
    Abstract:

    Background Although inhaled glucocorticoids are the mainstays of asthma treatment, they are poorly effective at treating and preventing virus-induced asthma exacerbations. The major viruses precipitating asthma exacerbations are Rhinoviruses. Objective We sought to evaluate whether Rhinovirus Infection interferes with the mechanisms of action of glucocorticoids. Methods Cultured primary human bronchial or transformed (A549) respiratory epithelial cells were infected with Rhinovirus 16 (RV-16) before dexamethasone exposure. Glucocorticoid receptor (GR) α nuclear translocation, glucocorticoid response element (GRE) binding, and transactivation/transrepression functional readouts were evaluated by using immunocytochemistry, Western blotting, DNA binding assays, real-time quantitative PCR, coimmunoprecipitation, and ELISA techniques. Specific inhibitors of c-Jun N-terminal kinase (JNK) and of IκB kinase (IKK) were used to investigate the involvement of intracellular signaling pathways. Results RV-16 Infection impaired dexamethasone-dependent (1) inhibition of IL-1β–induced CXCL8 release, (2) induction of mitogen-activated protein kinase phosphatase 1 gene expression, and (3) binding of GR to GREs in airway epithelial cells. This was associated with impaired GRα nuclear translocation, as assessed by means of both immunochemistry (54.0% ± 6.8% vs 24.7% ± 3.8% GR-positive nuclei after 10 nmol/L dexamethasone treatment in sham- or RV-16–infected cells, respectively; P Conclusion RV-16 Infection of human airway epithelium induces glucocorticoid resistance. Inhibition of RV-16–induced JNK and nuclear factor κB activation fully reversed Rhinovirus impairment of both GRα nuclear translocation and the transactivation/transrepression activities of glucocorticoids.

  • neutrophil adhesion molecules in experimental Rhinovirus Infection in copd
    Respiratory Research, 2013
    Co-Authors: Simon D Message, Katrina Gray, Aurica G Telcian, Marco Contoli, Patrick Mallia, Vasile Lazastanca
    Abstract:

    COPD exacerbations are associated with neutrophilic airway inflammation. Adhesion molecules on the surface of neutrophils may play a key role in their movement from blood to the airways. We analysed adhesion molecule expression on blood and sputum neutrophils from COPD subjects and non-obstructed smokers during experimental Rhinovirus Infections. Blood and sputum were collected from 9 COPD subjects and 10 smoking and age-matched control subjects at baseline, and neutrophil expression of the adhesion molecules and activation markers measured using flow cytometry. The markers examined were CD62L and CD162 (mediating initial steps of neutrophil rolling and capture), CD11a and CD11b (required for firm neutrophil adhesion), CD31 and CD54 (involved in neutrophil transmigration through the endothelial monolayer) and CD63 and CD66b (neutrophil activation markers). Subjects were then experimentally infected with Rhinovirus-16 and repeat samples collected for neutrophil analysis at post-Infection time points. At baseline there were no differences in adhesion molecule expression between the COPD and non-COPD subjects. Expression of CD11a, CD31, CD62L and CD162 was reduced on sputum neutrophils compared to blood neutrophils. Following Rhinovirus Infection expression of CD11a expression on blood neutrophils was significantly reduced in both subject groups. CD11b, CD62L and CD162 expression was significantly reduced only in the COPD subjects. Blood neutrophil CD11b expression correlated inversely with inflammatory markers and symptom scores in COPD subjects. Following Rhinovirus Infection neutrophils with higher surface expression of adhesion molecules are likely preferentially recruited to the lungs. CD11b may be a key molecule involved in neutrophil trafficking in COPD exacerbations.

Jie Zhu - One of the best experts on this subject based on the ideXlab platform.

  • bronchial mucosal ifn α β and pattern recognition receptor expression in patients with experimental Rhinovirus induced asthma exacerbations
    The Journal of Allergy and Clinical Immunology, 2019
    Co-Authors: Jie Zhu, Simon D Message, Tatiana Kebadze, Marco Contoli, Patrick Mallia, Christine K Ward
    Abstract:

    Background The innate immune system senses viral Infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in Rhinovirus-induced asthma exacerbations in vivo are uncertain. Objectives We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after Rhinovirus Infection in atopic asthmatic patients and control subjects. Methods Immunohistochemistry was used to detect expression of IFN-α, IFN-β, and the PRRs: Toll-like receptor 3, melanoma differentiation–associated gene 5, and retinoic acid–inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after Rhinovirus Infection. Results We observed IFN-α/β deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-α/β expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during Rhinovirus Infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/β in asthmatic patients during Infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during Rhinovirus Infection. Rhinovirus Infection–increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. Conclusions Bronchial epithelial IFN-α/β expression and numbers of subepithelial IFN-α/β–expressing monocytes/macrophages during Infection were both deficient in asthmatic patients. Lower epithelial IFN-α/β expression was associated with adverse clinical outcomes after Rhinovirus Infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during Infection were also related to greater viral load/illness severity.

  • il 33 dependent type 2 inflammation during Rhinovirus induced asthma exacerbations in vivo
    American Journal of Respiratory and Critical Care Medicine, 2014
    Co-Authors: David J. Jackson, Heidi Makrinioti, Betty Shamji, Jerico Delrosario, Aurica G Telcian, Alexandra Nikonova, Mariabelen Trujillotorralbo, Batika M J Rana, Joseph Footitt, Jie Zhu
    Abstract:

    Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell–derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation. Objectives: To assess whether Rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway. Methods: We used a human experimental model of Rhinovirus Infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a Rhinovirus Infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of Rhinovirus-infected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade. Measurements and Main Results: IL-4, IL-5, IL-13, and IL-33 are all induced by Rhinovirus in the asthmatic airway in vivo and relate to exacerbation severity. Further, induction of IL-33 correlates with viral load and IL-5 and IL-13 levels. Rhinovirus Infection of human primary BECs induced IL-33, and culture of human T cells and ILC2s with supernatants of Rhinovirus-infected BECs strongly induced type 2 cytokines. This induction was entirely dependent on IL-33. Conclusions: IL-33 and type 2 cytokines are induced during a Rhinovirus-induced asthma exacerbation in vivo. Virus-induced IL-33 and IL-33–responsive T cells and ILC2s are key mechanistic links between viral Infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbations.

  • co ordinated role of tlr3 rig i and mda5 in the innate response to Rhinovirus in bronchial epithelium
    PLOS Pathogens, 2010
    Co-Authors: Louise Slater, Ross P Walton, J J Haas, Simon D Message, Annemarie Sykes, Samer Dahdaleh, Deborah L Clarke, Nathan W. Bartlett, Jie Zhu, Maria G. Belvisi
    Abstract:

    The relative roles of the endosomal TLR3/7/8 versus the intracellular RNA helicases RIG-I and MDA5 in viral Infection is much debated. We investigated the roles of each pattern recognition receptor in Rhinovirus Infection using primary bronchial epithelial cells. TLR3 was constitutively expressed; however, RIG-I and MDA5 were inducible by 8–12 h following Rhinovirus Infection. Bronchial epithelial tissue from normal volunteers challenged with Rhinovirus in vivo exhibited low levels of RIG-I and MDA5 that were increased at day 4 post Infection. Inhibition of TLR3, RIG-I and MDA5 by siRNA reduced innate cytokine mRNA, and increased Rhinovirus replication. Inhibition of TLR3 and TRIF using siRNA reduced Rhinovirus induced RNA helicases. Furthermore, IFNAR1 deficient mice exhibited RIG-I and MDA5 induction early during RV1B Infection in an interferon independent manner. Hence anti-viral defense within bronchial epithelium requires co-ordinated recognition of Rhinovirus Infection, initially via TLR3/TRIF and later via inducible RNA helicases.

  • mouse models of Rhinovirus induced disease and exacerbation of allergic airway inflammation
    Nature Medicine, 2008
    Co-Authors: Nathan W. Bartlett, Ross P Walton, Juliya Aniscenko, Nicholas Glanville, Katherine Choy, Patrick Jourdan, Gaetano Caramori, Jie Zhu, Michael R. Edwards, Jerome Burnet
    Abstract:

    Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for Rhinovirus Infection. Of the 100 known Rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of Rhinovirus Infection: minor-group Rhinovirus Infection of BALB/c mice, major-group Rhinovirus Infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and Rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in Rhinovirus Infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations.