Impaired innate interferon induction in severe therapy resistant atopic asthmatic children.
TL;DR: It is shown that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-β and interferons-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation, and this is a feature of STRA.
About: This article is published in Mucosal Immunology.The article was published on 2013-07-01 and is currently open access. It has received 189 citations till now. The article focuses on the topics: Interferon.
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01 Jan 2020
TL;DR: Patients with severe asthma generally start to experience symptoms earlier than those with mild/moderate disease and have early development of atopy and a T2-like diathesis.
Abstract: Severe asthma affects approximately 1 in 20 asthmatics, and the healthcare resources utilization and mortality are disproportionately high in these patients. Deaths from asthma are relatively rare and correlate poorly with prevalence, and many patients who die from asthma are classified as having a mild/moderate disease based upon their treatment requirements. One of the challenges to understanding the epidemiology, pathophysiology, and etiology of severe asthma is its heterogeneity. Reasons for poor symptom control among patients on maximum treatment range from the wrong diagnosis to nonadherence with prescribed treatments and genuinely therapy-resistant disease. Social and personal circumstances often determine that patients do not adhere to asthma treatments, and this presents to caregivers with uncontrolled asthma. Patients with severe asthma generally start to experience symptoms earlier than those with mild/moderate disease and have early development of atopy and a T2-like diathesis. Severe asthma is often associated with comorbid condition, including obesity, rhinitis, nasal polyps, food allergy, and vocal cord dysfunction. An important determinant of severe asthma is a predisposition to the development of severe exacerbations. Genetic factors and host innate immune responses to viruses may be important determinants of asthma severity and exacerbations. History of sinusitis and of gastroesophageal reflux is associated with proneness for exacerbations. Severe childhood asthma is associated with a loss of lung function during childhood and is a major determinant of early-onset COPD. Therefore, prevention of severe childhood asthma ought to be a major component of the efforts to decrease early mortality due to COPD.
1 citations
TL;DR: In this paper , the influence of pre-existing airway inflammation on the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown.
Abstract: Rhinoviruses and allergens, such as house dust mite are major agents responsible for asthma exacerbations. The influence of pre-existing airway inflammation on the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. We analyse mechanisms of response to viral infection in experimental in vivo rhinovirus infection in healthy controls and patients with asthma, and in in vitro experiments with house dust mite, rhinovirus and SARS-CoV-2 in human primary airway epithelium. Here, we show that rhinovirus infection in patients with asthma leads to an excessive RIG-I inflammasome activation, which diminishes its accessibility for type I/III interferon responses, leading to their early functional impairment, delayed resolution, prolonged viral clearance and unresolved inflammation in vitro and in vivo. Pre-exposure to house dust mite augments this phenomenon by inflammasome priming and auxiliary inhibition of early type I/III interferon responses. Prior infection with rhinovirus followed by SARS-CoV-2 infection augments RIG-I inflammasome activation and epithelial inflammation. Timely inhibition of the epithelial RIG-I inflammasome may lead to more efficient viral clearance and lower the burden of rhinovirus and SARS-CoV-2 infections.
1 citations
01 Jan 2016
1 citations
Dissertation•
01 Jan 2018
TL;DR: A novel 3D culture method was used to mimic a real-life airway epithelium and found that COPD results in a switch in the type of interferon the cells produce, which has an effect on the antiviral response and will inform the use ofinterferon as a treatment.
Abstract: This project was an investigation of the antiviral response of lung cells from people with chronic obstructive pulmonary disease (COPD). A novel 3D culture method was used to mimic a real-life airway epithelium. By using this model we found that COPD results in a switch in the type of interferon the cells produce, which has an effect on the antiviral response and will inform the use of interferon as a treatment.
1 citations
Cites background or result from "Impaired innate interferon inductio..."
...Similarly to research in the asthma field, the exact role of the antiviral response of the airway epithelium in COPD is not clear, as some research has identified innate immune defects associated with COPD (113, 149), while others have conversely identified elevated antiviral factors, such as IFN-λ associated with viral infections in COPD (106, 107)....
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...Some of these studies suggest a defect in IFN-β and λ production (106), however studies by our group and others do not support this as an overall reason for susceptibility to all viruses (110-112)....
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...It is well known that asthmatics are more susceptible to lower respiratory viral infection due to defects in IFN-driven innate immunity, mostly within circulating immune cells (106, 107)....
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...The consensus in the literature currently concerning viral susceptibility of the asthmatic airway epithelium is that IFN defects are correlated only with severe asthma (106) and not mild to moderate asthma (112)....
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1 citations
References
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TL;DR: It is shown that different viruses are targeted by unique sets of ISGs, and that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities.
Abstract: The type I interferon response protects cells against invading viral pathogens. The cellular factors that mediate this defence are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery more than 25 years ago, only a few have been characterized with respect to antiviral activity. For most ISG products, little is known about their antiviral potential, their target specificity and their mechanisms of action. Using an overexpression screening approach, here we show that different viruses are targeted by unique sets of ISGs. We find that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities. To conduct the screen, more than 380 human ISGs were tested for their ability to inhibit the replication of several important human and animal viruses, including hepatitis C virus, yellow fever virus, West Nile virus, chikungunya virus, Venezuelan equine encephalitis virus and human immunodeficiency virus type-1. Broadly acting effectors included IRF1, C6orf150 (also known as MB21D1), HPSE, RIG-I (also known as DDX58), MDA5 (also known as IFIH1) and IFITM3, whereas more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT (also known as PBEF1), OASL, RTP4, TREX1 and UNC84B (also known as SUN2). Combined expression of pairs of ISGs showed additive antiviral effects similar to those of moderate type I interferon doses. Mechanistic studies uncovered a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E and MCOLN2, enhanced the replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic type I interferon system.
1,926 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
TL;DR: A few common alleles are associated with disease risk at all ages and suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation in asthma.
Abstract: A b s t r ac t Background Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. Methods We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. Results We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P =3×10 −9 ); rs9273349 on chromosome 6, implicating HLA-DQ (P = 7×10 −14 ); rs1342326 on chromosome 9, flanking IL33 (P = 9×10 −10 ); rs744910 on chromosome 15 in SMAD3 (P = 4×10 −9 ); and rs2284033 on chromosome 22 in IL2RB (P = 1.1×10 −8 ). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P = 6×10 −23 ). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. Conclusions Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)
1,764 citations
"Impaired innate interferon inductio..." refers background in this paper
...Array studies(22) have not found that these pattern recognition receptors are poorly expressed in asthma, and large genotyping studies have not highlighted any single-nucleotide polymorphisms associated with asthma for these genes.(41,42) These receptors also activate signaling pathways that are also common for pro-inflammatory cytokines,(18) which are not consistently reduced in studies where impaired IFN are observed....
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TL;DR: The identification of a ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state and may contribute to antiviral or other defenses by a mechanism similar to, but independent of, type I IFNs.
Abstract: We report here the identification of a ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state. Three closely positioned genes on human chromosome 19 encode distinct but paralogous proteins, which we designate interferon-lambda1 (IFN-lambda1), IFN-lambda2 and IFN-lambda3 (tentatively designated as IL-29, IL-28A and IL-28B, respectively, by HUGO). The expression of IFN-lambda mRNAs was inducible by viral infection in several cell lines. We identified a distinct receptor complex that is utilized by all three IFN-lambda proteins for signaling and is composed of two subunits, a receptor designated CRF2-12 (also designated as IFN-lambdaR1) and a second subunit, CRF2-4 (also known as IL-10R2). Both receptor chains are constitutively expressed on a wide variety of human cell lines and tissues and signal through the Jak-STAT (Janus kinases-signal transducers and activators of transcription) pathway. This receptor-ligand system may contribute to antiviral or other defenses by a mechanism similar to, but independent of, type I IFNs.
1,725 citations
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.
Abstract: Background The role of long-acting, inhaled β2-agonists in treating asthma is uncertain. In a double-blind study, we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide. Methods After a four-week run-in period of treatment with budesonide (800 μg twice daily), 852 patients being treated with glucocorticoids were randomly assigned to one of four treatments given twice daily by means of a dry-powder inhaler (Turbuhaler): 100 μg of budesonide plus placebo, 100 μg of budesonide plus 12 μg of formoterol, 400 μg of budesonide plus placebo, or 400 μg of budesonide plus 12 μg of formoterol. Terbutaline was permitted as needed. Treatment continued for one year; we compared the frequency of exacerbations of asthma, symptoms, and lung function in the four groups. A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days. Results T...
1,519 citations