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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TL;DR: In this article , the authors conducted a multicenter prospective study to determine the differences in the spectrum of viruses between adults with asthma exacerbations and AECOPD and assessed the prevalence and impact of human rhinovirus (HRV)-C in adults, which is more pathogenic in children with asthma than other HRV species.
Abstract: Viral respiratory infections are a common cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and asthma. We conducted a multicenter prospective study to determine the differences in the spectrum of viruses between adults with asthma exacerbations and AECOPD and assessed the prevalence and impact of human rhinovirus (HRV)-C in adults, which is more pathogenic in children with asthma than other HRV species.Nasopharyngeal and serum samples and clinical information were collected from 64 outpatients with adult asthma exacerbations and 44 outpatients with AECOPD between April 2018 and March 2020. Viral pathogens and HRV strains were identified from nasal samples by multiplex PCR and VP4/VP2 nested PCR.Viral pathogens were identified in 31 patients with asthma exacerbations (48.4%) and 17 patients with AECOPD (38.6%). The most commonly detected viruses were HRV/enterovirus followed by human metapneumovirus (hMPV) in patients with asthma exacerbations, and hMPV followed by parainfluenza virus in patients with AECOPD. HRV-C was the HRV species most commonly associated with both asthma exacerbations and AECOPD. Clinical characteristics, baseline lung function, serum inflammatory chemokines, hospitalization, and systemic steroid use did not differ between HRV-C-positive patients and those positive for other HRV species.Exacerbation-associated spectrum of viruses differed between adults with asthma exacerbations and AECOPD. HRV-C was the HRV species most often observed in adult asthma exacerbations and AECOPD, although it did not worsen patients' clinical outcomes relative to those of patients with other HRVs. Underlying disease-specific factors may be responsible for susceptibility to respiratory viruses.UMIN-CTR UMIN000031934.
5 citations
01 Jan 2019
TL;DR: The epidemiological evidence supports respiratory viruses including RV as triggers of exacerbations of chronic lung diseases and the latest mechanistic evidence supporting how and why common respiratory viral infections may enhance and promote disease triggering exacerbation events is highlighted.
Abstract: Respiratory viral infections including human rhinovirus (RV) infection have been identified as the most important environmental trigger of exacerbations of chronic lung diseases. While well established as the most common viral infections associated with exacerbations of asthma and chronic obstructive pulmonary disease, RVs and other respiratory viruses are also now thought to be important in triggering exacerbations of cystic fibrosis and the interstitial lung diseases. Here, we summarize the epidemiological evidence the supports respiratory viruses including RV as triggers of exacerbations of chronic lung diseases. We propose that certain characteristics of RVs may explain why they are the most common trigger of exacerbations of chronic lung diseases. We further highlight the latest mechanistic evidence supporting how and why common respiratory viral infections may enhance and promote disease triggering exacerbation events, through their interactions with the host immune system, and may be affected by ongoing treatments. We also provide a commentary on how new treatments may better manage the disease burden associated with respiratory viral infections and the exacerbation events that they trigger.
4 citations
Cites background from "Impaired innate interferon inductio..."
...150 This makes IFN therapy attractive as a therapy for AE, but complicates the interpretation of any positive effects; the fact that asthmatics may be defective in IFN induction 139, 142, 174, 175 further makes IFN-therapy attractive, but may additionally complicate the interpretation of trials with IFNs....
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Dissertation•
01 Jan 2016
TL;DR: Both in vitro and in vivo models are explored, revealing important and potential drug target molecules such as TSLP, IL-33 and IL-25 involved in triggering or maintaining of viral-triggered respiratory exacerbations.
Abstract: Exacerbations of asthma and COPD are mainly caused by viral infections, where majority are represented by the common cold, rhinovirus. These are severe acute episodes in the disease and need effective treatments. Worldwide, the huge economical burden and suffering of several hundred million of patients are in need of novel drugs to treat and prevent the high rate of morbidity and mortality. To develop novel treatments new models are needed, that can mimic clinical features of asthma and COPD exacerbations, to elucidate the molecular mechanisms involved in causing and maintaining respiratory exacerbations caused by viral infections. This thesis aims to develop in vivo models and also using both in vitro and in vivo settings to study exacerbations. The goal was then to further investigate drug interventions, or gene knockouts, to elucidate the mechanisms involved in the signalling pathways leading to exacerbations. For this purpose, primary human bronchial epithelaial cells (HBECs) and mice have been used. Firstly, primary HBECs donated from asthmatics and COPD patients were cultured and stimulated with a viral surrogate dsRNA, mimicking rhinoviral replication, inducing cytokine expression. Simultaneously drug substances were applied to study the anti-inflammatory effects while cytokine expression of TSLP, IFNβ, TNFα and CXCL8 was observed measuring both mRNA expression (RT-qPCR) and protein production (ELISA). Also transcription factors NF-κB and IRF3 were studied (Western blot). The substances tested were small-molecular inhibitors called RES as well as Capsazepine (CPZ) and Simvastatin. The further work in this thesis involved development of an asthma exacerbation model that involved allergen provoked allergic inflammation that was superimpose by dsRNA for induction of exacerbation. The allergen challenge involved Ovalbumin in the first study, while the other two studies involved house dust mite (HDM). Leukocytes in bronchoalveolar lavage fluid and lung tissue were studied, as well as gene expression (RT-qPCR) and protein release (ELISA, Immunohistochemistry) of various cytokines and induction of pattern recognition receptors; TLR3,RIG-I and MDA5. The last in vivo study explored the effects of gene knockout of pro-inflammatory IL-1β, while using HDM-triggered experimental asthma model with superimposed dsRNA-triggered exacerbation. The results showed that both CPZ and RES substances inhibit viral-induced cytokine production of TSLP as well as IFNβ in both HBECs from asthmatic and COPD patients. Also the pleotropic effects of Simvastatin explored in COPD HBECs stimulated with dsRNA, showed anti-inflammatory effects, where TSLP and IFNβ production was inhibited dose-dependently and more effectively compared to inhibition with steroids. RES and CPZ exerted their function through NF-κB inhibition while Simvastatin rather exerted its effects through IRF3. The asthma exacerbation model showed induction of Th2 upstream cytokines TSLP, IL-33 and IL-25 being significantly induced at exacerbation, giving synergistic effects from both allergic provocation and dsRNA. Also PPRs were shown to increase at exacerbation. The IL-1β knockout mice showed less inflammation and leukocyte tissue infiltration as well as less apoptosis and necrosis compared to wildtype mice. Most interestingly, the Th2 upstream cytokine induction in wild type mice seen at exacerbation was not altered in the KO mice. This thesis explored both in vitro and in vivo models, revealing important and potential drug target molecules such as TSLP, IL-33 and IL-25 involved in triggering or maintaining of viral-triggered respiratory exacerbations. Interestingly enough, IL-1β seems to be involved in the regulation of all three Th2 upstream cytokines in asthma exacerbation and might also serve as an option of treatments. Drug intervention using small-molecular inhibitors or already existing drugs possessing pleotropic effects, could be another considered option for future development of combination therapy.
4 citations
Cites background from "Impaired innate interferon inductio..."
...The interferon deficiency in asthmatics has been pointed out as an important reason for viral-induced exacerbations [267, 318, 357-360]....
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TL;DR: In this paper, a review examines the current literature and identifies the gaps in the field defining viral-induced effects on a vulnerable respiratory epithelium and resulting chronic inflammation drawing from knowledge generated in acute wheezing illness, paediatric asthma and Eosinophilic oesophagitis (EoE).
Abstract: The epithelium is integral to the protection of many different biological systems and for the maintenance of biochemical homeostasis. Emerging evidence suggests that particular children have epithelial vulnerabilities leading to dysregulated barrier function and integrity, that resultantly contributes to disease pathogenesis. These epithelial vulnerabilities likely develop in utero or in early life due to various genetic, epigenetic and environmental factors. Although various epithelia are uniquely structured with specific function, prevalent allergic-type epithelial diseases in children potentially have common or parallel disease processes. These include inflammation and immune response dysregulation stemming from atypical epithelial barrier function and integrity. Two diseases where aetiology and pathogenesis are potentially linked to epithelial vulnerabilities include Paediatric Asthma and Eosinophilic Oesophagitis (EoE). For example, rhinovirus C (RV-C) is a known risk factor for paediatric asthma development and is known to disrupt respiratory epithelial barrier function causing acute inflammation. In addition, EoE, a prevalent atopic condition of the oesophageal epithelium, is characterised by similar innate immune and epithelial responses to viral injury. This review examines the current literature and identify the gaps in the field defining viral-induced effects on a vulnerable respiratory epithelium and resulting chronic inflammation drawing from knowledge generated in acute wheezing illness, paediatric asthma and EoE. Besides highlighting the importance of epithelial structure and barrier function in allergic disease pathogenesis regardless of specific epithelial sub-types, this review identifies the importance to examine other parallel allergic-type disease processes that may uncover commonalities driving disease pathogenesis. This in turn may be helpful to develop common therapeutics for current clinical management and in the future disease prevention.
4 citations
01 Jan 2015
TL;DR: The endotyping of chronic rhinosinusitis makes use of tissue biomarkers to identify the dominant T helper cell and cytokine pattern, as well as related inflammatory processes for the selection of therapeutic interventions and the prediction of the likelihood of comorbidity.
Abstract: The mucosal layer of the upper airways is continuously exposed to microbes, irritants, and pollutants to which it needs to defend itself. Apart from mechanical components such as mucous secretion and the epithelial barrier, innate and adaptive immune mechanisms involving dendritic cells, macrophages, and T and B cells aim to maintain the integrity of the mucosa. However, viral infections of the upper airways, allergen exposure, bacterial colonization, eventual mucosal invasion, and the release of bacterial products impact heavily on the mucosal layer, leading to chronic diseases such as allergic rhinitis, chronic rhinosinusitis, and nasal polyposis. The diseases manifest themselves at different levels: mucosal remodeling, eosinophilic and neutrophilic types of inflammation, and, finally, asthma comorbidity. The endotyping of chronic rhinosinusitis makes use of tissue biomarkers to identify the dominant T helper cell and cytokine pattern, as well as related inflammatory processes for the selection of therapeutic interventions and the prediction of the likelihood of comorbidity.
4 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