Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus
21 Mar 2005-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 201, Iss: 6, pp 937-947
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.
Abstract: 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-beta mRNA expression in asthmatic cultures and they produced >2.5 times less interferon-beta protein. In infected asthmatic cells, exogenous interferon-beta induced apoptosis and reduced virus replication, demonstrating a causal link between deficient interferon-beta, 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.
Citations
More filters
01 Aug 2007
3,099 citations
National Institutes of Health1, University of Pittsburgh2, McMaster University3, University of Washington4, University of Cape Town5, Wake Forest University6, University of Leicester7, Karolinska Institutet8, University of Southampton9, Boston Children's Hospital10, John Hunter Hospital11, McGill University12, University of Wisconsin-Madison13, University of Virginia14
TL;DR: Recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults and coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy are provided.
Abstract: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.
2,795 citations
TL;DR: Results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans are discussed and the extraordinary heterogeneity of asthma is described.
Abstract: Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2 (T(H)2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the T(H)17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma.
1,268 citations
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.
Abstract: Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-λs by rhinovirus in asthmatic 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. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity. These results identify previously unknown mechanisms of susceptibility to infection in asthma and suggest new approaches to prevention and/or treatment of asthma exacerbations.
927 citations
TL;DR: Serum 25(OH)D levels are inversely associated with recent URTI, and this association may be stronger in those with respiratory tract diseases.
Abstract: Background Recent studies suggest a role for vitamin D in innate immunity, including the prevention of respiratory tract infections (RTIs). We hypothesize that serum 25-hydroxyvitamin D (25[OH]D) levels are inversely associated with self-reported recent upper RTI (URTI). Methods We performed a secondary analysis of the Third National Health and Nutrition Examination Survey, a probability survey of the US population conducted between 1988 and 1994. We examined the association between 25(OH)D level and recent URTI in 18 883 participants 12 years and older. The analysis adjusted for demographics and clinical factors (season, body mass index, smoking history, asthma, and chronic obstructive pulmonary disease). Results The median serum 25(OH)D level was 29 ng/mL (to convert to nanomoles per liter, multiply by 2.496) (interquartile range, 21-37 ng/mL), and 19% (95% confidence interval [CI], 18%-20%) of participants reported a recent URTI. Recent URTI was reported by 24% of participants with 25(OH)D levels less than 10 ng/mL, by 20% with levels of 10 to less than 30 ng/mL, and by 17% with levels of 30 ng/mL or more (P or =30 ng/mL: odds ratio [OR], 1.36; 95% CI, 1.01-1.84 for Conclusions Serum 25(OH)D levels are inversely associated with recent URTI. This association may be stronger in those with respiratory tract diseases. Randomized controlled trials are warranted to explore the effects of vitamin D supplementation on RTI.
913 citations
References
More filters
10,451 citations
TL;DR: This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children.
Abstract: Objective: To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community. Design: Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses. Subjects: 108 Children aged 9-11 years who had reported wheeze or cough, or both, in a questionnaire. Setting: Southampton and surrounding community. Main outcome measures: 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. Results: 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 1/min. The most commonly identified virus type was rhinovirus. Conclusions: This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children. Key messages Key messages In this study common cold viruses were found in 80-85% of reported exacerbations of asthma in children Rhinoviruses, which cause most common colds, accounted for two thirds of viruses detected Analysis of diary cards also showed large numbers of similar but less severe episodes that may also be viral in origin
1,889 citations
"Asthmatic bronchial epithelial cell..." refers background in this paper
...ICSs-naive asthma; 10 nM 772 (581, 1,220) compared with ICSs-naive...
[...]
...Viral respiratory tract infections are responsible for up to 85% of asthma exacerbations (1, 2), with the most severe requiring hospitalization (3)....
[...]
...IFN- levels were significantly reduced at 721 (464, 1,290) pg/ml, compared...
[...]
...In healthy control cells; 10 nM 1717 (720, 1,990) compared with infected...
[...]
...For asthmatic BECs, median (IQR) IFN- levels were significantly reduced at 721 (464, 1,290) pg/ml, compared with 1,854 pg/ml (758, 3,766; P 0....
[...]
TL;DR: The results demonstrate the essential and distinct roles of the two factors, which together ensure the transcriptional efficiency and diversity of IFN-alpha/beta genes for the antiviral response.
1,266 citations
TL;DR: It is shown that asthma symptoms and reductions in peak flow are often associated with colds and respiratory viruses; respiratory virus infections commonly cause or are associated with exacerbations of asthma in adults.
Abstract: OBJECTIVE--To study the role of respiratory viruses in exacerbations of asthma in adults. DESIGN--Longitudinal study of 138 adults with asthma. SETTING--Leicestershire Health Authority. SUBJECTS--48 men and 90 women 19-46 years of age with a mean duration of wheeze of 19.6 years. 75% received regular treatment with bronchodilators; 89% gave a history of eczema, hay fever, allergic rhinitis, nasal polyps, or allergies; 38% had been admitted to hospital with asthma. MAIN OUTCOME MEASURES--Symptomatic colds and asthma exacerbations; objective exacerbations of asthma with > or = 50 l/min reduction in mean peak expiratory flow rate when morning and night time readings on days 1-7 after onset of symptoms were compared with rates during an asymptomatic control period; laboratory confirmed respiratory tract infections. RESULTS--Colds were reported in 80% (223/280) of episodes with symptoms of wheeze, chest tightness, or breathlessness, and 89% (223/250) of colds were associated with asthma symptoms. 24% of 115 laboratory confirmed non-bacterial infections were associated with reductions in mean peak expiratory flow rate > or = 50 l/min through days 1-7 and 48% had mean decreases > or = 25 l/min. 44% of episodes with mean decreases in flow rate > or = 50 l/min were associated with laboratory confirmed infections. Infections with rhinoviruses, coronaviruses OC43 and 229E, influenza B, respiratory syncytial virus, parainfluenza virus, and chlamydia were all associated with objective evidence of an exacerbation of asthma. CONCLUSIONS--These findings show that asthma symptoms and reductions in peak flow are often associated with colds and respiratory viruses; respiratory virus infections commonly cause or are associated with exacerbations of asthma in adults.
1,119 citations
"Asthmatic bronchial epithelial cell..." refers background in this paper
...Viral respiratory tract infections are responsible for up to 85% of asthma exacerbations (1, 2), with the most severe requiring hospitalization (3)....
[...]
TL;DR: It is shown that transcription of the p53 gene is induced by IFN-α/β, accompanied by an increase in p53 protein level, and that p53 is critical for antiviral defence of the host.
Abstract: Swift elimination of undesirable cells is an important feature in tumour suppression and immunity. The tumour suppressor p53 and interferon-α and -β (IFN-α/β) are essential for the induction of apoptosis in cancerous cells and in antiviral immune responses, respectively, but little is known about their interrelationship. Here we show that transcription of the p53 gene is induced by IFN-α/β, accompanied by an increase in p53 protein level. IFN-α/β signalling itself does not activate p53; rather, it contributes to boosting p53 responses to stress signals. We show examples in which p53 gene induction by IFN-α/β contributes to tumour suppression. Furthermore, we show that p53 is activated in virally infected cells to evoke an apoptotic response and that p53 is critical for antiviral defence of the host. Our study reveals a hitherto unrecognized link between p53 and IFN-α/β in tumour suppression and antiviral immunity, which may have therapeutic implications.
836 citations
"Asthmatic bronchial epithelial cell..." refers background in this paper
...Release of interferon- from BECs after infection Because IFN- / has recently been shown to induce apoptotic responses in antiviral immunity (11), and because IFNis known to be secreted first and to strongly induce the IFN- subfamily (15), we investigated whether impaired production of IFN- was the underlying mechanism regulating the abnormal antiviral response in asthmatic cells....
[...]
...Rapid induction of apoptosis in virusinfected host cells is a critical component of innate antiviral responses (11), as early apoptosis prevents establishment of viral replication and promotes phagocytosis of infected cells....
[...]
...Type I interferons have also been shown to induce apoptosis via activation of the tumor suppressor gene p53 in response to vesicular stomatitis virus infection in mice, further enhancing antiviral activity (11) and demonstrating that early apoptosis is a key protective innate immune antiviral response....
[...]
...Recently they have been linked to apoptotic responses to virus infections in antiviral defense (11)....
[...]