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: This study demonstrates that treatment with rupintrivir influences virus-induced IL-4 and IL-6 cytokine release under experimental conditionsEx vivo, and inhibits exaggerated pro-inflammatory cytokine IL-2 and TH-2 in HDM-sensitized mice.
Abstract: Antiviral drugs such as rupintrivir may have an immune-modulatory effect in experimentally induced allergic asthma with subsequent RV infection. We infected lung slices of house-dust mite (HDM)-sensitized asthmatic mice ex vivo with human rhinovirus (RV) and investigated the effect of the antiviral drug rupintrivir on RV-induced cytokine response in lung tissue of HDM-sensitized mice ex vivo. Mice were sensitized with HDM. Precision-cut lung slices (PCLS) were prepared from HDM-sensitized or non-sensitized mice. Lung slices were infected ex vivo with RV or RV together with rupintrivir. Modulation of immune responses was evaluated by cytokine secretion 48 h post infection. In vivo HDM sensitization resulted in a TH-2/TH-17-dominated cytokine response that persisted in PCLS ex vivo. RV infection of PCLS from non-sensitized mice resulted in the induction of an antiviral and pro-inflammatory immune response, as indicated by the secretion of IFN-α, IFN-β, IFN-γ, TNF-α, MCP-1, IP-10, IL-10, and IL-17A. In contrast, PCLS from HDM-sensitized mice showed an attenuated antiviral response, but exaggerated IL-4, IL-6, and IL-10 secretion upon infection. Rupintrivir inhibited exaggerated pro-inflammatory cytokine IL-6 and TH-2 cytokine IL-4 in HDM-sensitized mice. In summary, this study demonstrates that treatment with rupintrivir influences virus-induced IL-4 and IL-6 cytokine release under experimental conditions ex vivo.
9 citations
TL;DR: In this paper , the authors explored the innate immune response in the upper airway of volunteers with allergic rhinitis and asthma in comparison to healthy controls and interrogated how these differences corresponded to severity of infection.
Abstract: Viral infections, especially those caused by rhinovirus, are the most common cause of asthma exacerbations. Previous studies have argued that impaired innate antiviral immunity and, as a consequence, more severe infections contribute to these exacerbations.These studies explored the innate immune response in the upper airway of volunteers with allergic rhinitis and asthma in comparison to healthy controls and interrogated how these differences corresponded to severity of infection.Volunteers with allergic rhinitis, those with asthma, and those who are healthy were inoculated with rhinovirus A16 and monitored for clinical symptoms. Tissue and nasal wash samples were evaluated for antiviral signature and viral load.Both subjects with allergic rhinitis and asthma were found to have more severe cold symptoms. Subjects with asthma had worsened asthma control and increased bronchial hyperreactivity in the setting of higher fractional exhaled breath nitric oxide and blood eosinophils. These studies confirmed reduced expression of interferons and virus-specific pattern recognition receptors in both cohorts with atopy. Nevertheless, despite this defect in innate immunity, volunteers with allergic rhinitis/asthma had reduced rhinovirus concentrations in comparison to the controls.These results confirm that the presence of an allergic inflammatory disorder of the airway is associated with reduced innate immune responsive to rhinovirus infection. Despite this, these volunteers with allergy have reduced viral loads, arguing for the presence of a compensatory mechanism to clear the infection.ClinicalTrials.gov Identifier: NCT02910401.
8 citations
TL;DR: The data suggest that IC87114 may promote virus elimination and clearance through PD-L1 downregulation and enhanced antiviral IFN responses, preventing prolonged lung inflammation, which exacerbates asthma and COPD.
Abstract: Viral infections of the airway can exacerbate respiratory diseases, such as asthma or chronic obstructive pulmonary disease (COPD), and accelerate disease progression. Phosphoinositide 3-kinase (PI3K)δ, a class 1A PI3K, has been studied as a potential target for achieving anti-oncogenic and anti-inflammatory effects. However, the role of PI3Kδ in antiviral responses is poorly understood. Using a synthetic double-stranded RNA poly I:C and a selective PI3Kδ inhibitor IC87114, we investigated the role of PI3Kδ signaling in poly I:C-induced expression of the T lymphocyte-inhibitory molecule programmed death 1 ligand 1 (PD-L1), inflammatory responses and antiviral interferon (IFN) responses. C57BL/6N mice were treated with IC87114 or vehicle by intratracheal (i.t.) instillation followed by i.t. administration of poly I:C. Poly I:C increased PD-L1 expression on epithelial cells, lymphocytes, macrophages, and neutrophils in the lungs and IC87114 suppressed poly I:C-induced PD-L1 expression on epithelial cells and neutrophils possibly via inhibition of the Akt/mTOR signaling pathway. IC87114 also attenuated poly I:C-induced increases in numbers of total cells, macrophages, neutrophils and lymphocytes, as well as levels of KC, IL-6 and MIP-1β in bronchoalveolar lavage fluid. Gene expression of IFNβ, IFNλ2 and IFN-stimulated genes (ISGs) were upregulated in response to poly I:C and a further increase in gene expression was observed following IC87114 treatment. In addition, IC87114 enhanced poly I:C-induced phosphorylation of IRF3. We assessed the effects of IC87114 on human primary bronchial epithelial cells (PBECs). IC87114 decreased poly I:C-induced PD-L1 expression on PBECs and secretion of IL-6 and IL-8 into culture supernatants. IC87114 further enhanced poly I:C- induced increases in the concentrations of IFNβ and IFNλ1/3 in culture supernatants as well as upregulated gene expression of ISGs in PBECs. Similar results were obtained in PBECs transfected with siRNA targeting the PIK3CD gene encoding PI3K p110δ, and stimulated with poly I:C. In human metapneumovirus (hMPV) infection of PBECs, IC87114 suppressed hMPV-induced PD-L1 expression and reduced viral replication without changing the production levels of IFNβ and IFNλ1/3 in culture supernatants. These data suggest that IC87114 may promote virus elimination and clearance through PD-L1 downregulation and enhanced antiviral IFN responses, preventing prolonged lung inflammation, which exacerbates asthma and COPD.
8 citations
Cites background or methods from "Impaired innate interferon inductio..."
...Impaired antiviral IFN responses in asthmatic PBECs were also reported (64, 65)....
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...The studies involving human participants were reviewed and approved by the Kyushu University Institutional Review Board for Clinical Research....
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...The study protocol was approved by the Kyushu University Institutional Review Board for Clinical Research (29-170)....
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TL;DR: In this paper , a composite type-2 biomarker of blood eosinophils and fractional exhaled nitric oxide was used to predict severe asthma attacks in both adult and pediatric patients.
Abstract: Among patients with asthma, reliance on the type/dose of prescribed medication and symptom control does not adequately capture those at risk of adverse outcomes, and we need biomarkers for risk and treatment stratification that are consistently accurate, readily quantifiable, and reproducible. Most patients with severe asthma, regardless of age, have predominant type-2 inflammation-mediated disease, making airway/blood eosinophils, fractional exhaled nitric oxide, periostin, and/or allergic sensitization potentially important biomarkers for severe disease. In both adult and pediatric asthma, there is scope to improve prediction of severe attacks by using a composite type-2 biomarker of blood eosinophils and fractional exhaled nitric oxide. Technological advances in component-resolved diagnostics microarray technologies coupled with the development of interpretation software offer a possibility to use component-resolved diagnostics as biomarkers of asthma severity among sensitized patients with asthma. Genetic predisposition and polygenic risk scores of relevant traits (eg, lung function, host immune responses, biomarkers of exposure from the indoor and outdoor environment, infection, and microbial dysbiosis) may also contribute to prediction algorithms. We challenge the idea that asthma can be accurately defined in an individual patient by a discrete and static "endotype" (eg, type-2-high asthma). As we traverse the new era of molecular endotyping in asthma, we need to understand how relevant mechanisms impact patient outcomes, and in parallel develop new tools and approaches to stratify therapies and define individual patient trajectories.
8 citations
TL;DR: Absence of symptoms of respiratory tract infection notwithstanding, HRV seems to be more prevalent in the airways of adolescents and young adults with asthma and a high degree of aeroallergen IgE sensitisation than in controls.
8 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