Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production.
Simon D. Message,Vasile Laza-Stanca,Patrick Mallia,Hayley L. Parker,Jie Zhu,Tatiana Kebadze,Marco Contoli,Gwen Sanderson,Onn Min Kon,Alberto Papi,Peter K. Jeffery,Luminita A. Stanciu,Sebastian L. Johnston +12 more
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TLDR
Increased RV-induced clinical illness severity in asthmatic compared with normal subjects is demonstrated, evidence of strong relationships between virus load, lower airway virus-induced inflammation and asthma exacerbation severity is provided, and indicates augmented Th2 or impaired Th1 or IL-10 immunity are likely important mechanisms.Abstract:
Acute exacerbations are the major cause of asthma morbidity, mortality, and health-care costs and are difficult to treat and prevent. The majority of asthma exacerbations are associated with rhinovirus (RV) infection, but evidence supporting a causal relationship is weak and mechanisms are poorly understood. We hypothesized that in asthmatic, but not normal, subjects RV infection would induce clinical, physiologic, and pathologic lower airway responses typical of an asthma exacerbation and that these changes would be related to virus replication and impaired T helper 1 (Th1)/IL-10 or augmented Th2 immune responses. We investigated physiologic, virologic, and immunopathologic responses to experimental RV infection in blood, induced sputum, and bronchial lavage in 10 asthmatic and 15 normal volunteers. RV infection induced significantly greater lower respiratory symptoms and lung function impairment and increases in bronchial hyperreactivity and eosinophilic lower airway inflammation in asthmatic compared with normal subjects. In asthmatic, but not normal, subjects virus load was significantly related to lower respiratory symptoms, bronchial hyperreactivity, and reductions in blood total and CD8+ lymphocytes; lung function impairment was significantly related to neutrophilic and eosinophilic lower airway inflammation. The same virologic and clinical outcomes were strongly related to deficient IFN-γ and IL-10 responses and to augmented IL-4, IL-5, and IL-13 responses. This study demonstrates increased RV-induced clinical illness severity in asthmatic compared with normal subjects, provides evidence of strong relationships between virus load, lower airway virus-induced inflammation and asthma exacerbation severity, and indicates augmented Th2 or impaired Th1 or IL-10 immunity are likely important mechanisms.read more
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Journal ArticleDOI
CXCR2 Is Required for Neutrophilic Airway Inflammation and Hyperresponsiveness in a Mouse Model of Human Rhinovirus Infection
Deepti R. Nagarkar,Qiong Wang,Jee Shim,Ying Zhao,Wan C. Tsai,Nicholas W. Lukacs,Uma S. Sajjan,Marc B. Hershenson +7 more
TL;DR: It is concluded that CXCR2 is required for RV-induced neutrophilic airway inflammation and that neutrophil TNF-α release is needed for airway hyperresponsiveness.
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Azithromycin for Acute Exacerbations of Asthma : The AZALEA Randomized Clinical Trial.
Sebastian L. Johnston,Matyas Szigeti,Mary Cross,Christopher E. Brightling,Rekha Chaudhuri,Rekha Chaudhuri,Tim Harrison,Adel H. Mansur,Adel H. Mansur,Laura Robison,Zahid Sattar,David A. Jackson,Patrick Mallia,Ernie Wong,Christopher Corrigan,Christopher Corrigan,Bernard Higgins,P. W. Ind,P. W. Ind,Dave Singh,Neil C. Thomson,Deborah Ashby,Anoop Chauhan,Azalea, Trial, Team +23 more
TL;DR: In this randomized population, azithromycin treatment resulted in no statistically or clinically significant benefit and no significant between-group differences were observed in quality-of-life questionnaires or lung function between exacerbation and day 10, or in time to 50% reduction in symptom score.
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Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity.
TL;DR: It is shown for the first time that rhinovirus can infect neuronal cells and infection causes upregulation of TRP channels by channel-specific mechanisms, which may be novel therapeutic targets for controlling virus-induced cough.
Journal ArticleDOI
Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor κB and c-Jun N-terminal kinase activation.
Alberto Papi,Marco Contoli,Ian M. Adcock,Cinzia M. Bellettato,Cinzia M. Bellettato,Anna Padovani,Paolo Casolari,Luminita A. Stanciu,Peter J. Barnes,Sebastian L. Johnston,Kazuhiro Ito,Gaetano Caramori +11 more
TL;DR: RV-16 infection of human airway epithelium induces glucocorticoid resistance and the combination of JNK and IKK2 inhibitors totally restored dexamethasone suppression of CXCL8 release, induction of mitogen-activated protein kinase phosphatase 1 gene expression, and GRα nuclear translocation.
References
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Sebastian L. Johnston,Philip Pattemore,G. Sanderson,Sandra Smith,F Lampe,Lynn Josephs,P. Symington,S. O'Toole,S. H. Myint,D. A. J. Tyrrell +9 more
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Romain Pauwels,Claes-Göran Löfdahl,Dirkje S. Postma,Anne E. Tattersfield,Paul M. O'Byrne,Peter J. Barnes,A Ullman +6 more
TL;DR: In patients who have persistent symptoms of asthma despite treatment with inhaled glucocorticoids, the addition of formoterol to budesonid therapy or the use of a higher dose of budesonide may be beneficial.
Journal ArticleDOI
Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus
Peter A. B. Wark,Sebastian L. Johnston,Fabio Bucchieri,Robert M. Powell,Sarah M. Puddicombe,Vasile Laza-Stanca,Stephen T. Holgate,Donna E. Davies +7 more
TL;DR: A causal link between deficient interferon-β, impaired apoptosis and increased virus replication is demonstrated, suggesting a novel use for type I interferons in the treatment or prevention of virus-induced asthma exacerbations.
Journal ArticleDOI
Role of deficient type III interferon-λ production in asthma exacerbations
Marco Contoli,Simon D. Message,Vasile Laza-Stanca,Michael R. Edwards,Peter A. B. Wark,Peter A. B. Wark,Nathan W. Bartlett,Tatiana Kebadze,Patrick Mallia,Luminita A. Stanciu,Hayley L. Parker,Louise Slater,Anita Lewis-Antes,Onn Min Kon,Stephen T. Holgate,Donna E. Davies,Sergei V. Kotenko,Alberto Papi,Sebastian L. Johnston +18 more
TL;DR: In this paper, the authors show deficient induction of interferon-λs by rhinovirus in primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus induced asthma exacerbation and virus load in experimentally infected human volunteers.
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