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 review summarizes the common pathophysiological background of asthma and infections, highlighting the importance of an underlying immune system defect that predispose individuals to recurrent infections and asthma.
Abstract: Asthma is a heterogeneous chronic respiratory disease characterized by an increased burden of infections. Respiratory tract infections associated with an increased risk for asthma especially when occurring in the first months of life, also represent the most common cause of asthma exacerbations. The association between asthma and the increased frequency of infections and microbiota dysbiosis might be explained by a common mechanism, such as an underlying immune system defect. Apart from the well-established association between primary immunodeficiencies and asthma, several alterations in the immune response following infection have also been observed in asthmatic patients. An impairment in lung epithelial barrier integrity exists and is associated with both an increased susceptibility to infections and the development of asthma. Asthmatic patients are also found to have a deficient interferon (IFN) response upon infection. Additionally, defects in Toll-like receptor (TLR) signaling are observed in asthma and are correlated with both recurrent infections and asthma development. In this review, we summarize the common pathophysiological background of asthma and infections, highlighting the importance of an underlying immune system defect that predispose individuals to recurrent infections and asthma.
11 citations
Cites background from "Impaired innate interferon inductio..."
...Abbreviations: ADAM33: disintegrin and metalloprotease domain 33; BAL: bronchoalveolar lavage; ; BECs: bronchial epithelial cells; ; CVID: common variable immunodeficiency; ; EGF: epidermal growth factor; ; GSDMB: gasdermin B; ; HRV: human rhinovirus; ; IFN: interferon; ; IL-1R: interleukin-1 receptor; ; IPEX: immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; ; IRAK: interleukin 1 receptor associated kinase; ; HAART: highly active antiretroviral therapy; ; HIV: human immunodeficiency virus; ; mAb: monoclonal antibody; ; MD-1: myeloid differentiation-1; ; NF-kB: nuclear factor-kB; ; PBMCs: peripheral blood mononuclear cells; ; pDCs: plasmacytoid dendritic cells; ; RSV: respiratory syncytial virus; ; sIgAD: selective IgA deficiency; ; ORMDL3: sphingolipid biosynthesis regulator 3; ; SNPs: single nuclear polymorphisms; ; SPINK: serine protease inhibitors of the Kazal type; ; SOCS: suppressor of cytokine signaling; ; TGF: transforming growth factor; ; Th1, 2: T-helper 1, 2; ; TLR: toll-like receptor ARTICLE HISTORY Received 25 September 2018 Accepted 12 February 2019 KEYWORDS Asthma; infection; interferons; microbiota; Tolllike receptors...
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...Studies show also a decrease of IFN production upon Newcastle disease virus infection from PBMCs and upon influenza virus infection from purified plasmacytoid dendritic cells (pDCs) in asthmatic patients [20]....
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...This alteration has been observed in both peripheral blood mononuclear cells (PBMCs) and in macrophages from bronchoalveolar lavage (BAL) [20]....
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...21 TGF Increased in BAL fluid and endobronchial biopsy specimens in asthmatic patients, inhibits IFN production and enhances respiratory tract viral infection....
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DOI•
11 Nov 2020TL;DR: There has been significant recent progress in understanding of the mechanisms underlying virus-induced airway inflammation in asthma and these advances will underpin the development of future clinical therapies.
Abstract: In this review, we discuss the latest developments in research pertaining to virus-induced asthma exacerbations and consider recent advances in treatment options. Asthma is a chronic disease of the airways that continues to impose a substantial clinical burden worldwide. Asthma exacerbations, characterised by an acute deterioration in respiratory symptoms and airflow obstruction, are associated with significant morbidity and mortality. These episodes are most commonly triggered by respiratory virus infections. The mechanisms underlying the pathogenesis of virus-induced exacerbations have been the focus of extensive biomedical research. Developing a robust understanding of the interplay between respiratory viruses and the host immune response will be critical for developing more efficacious, targeted therapies for exacerbations. CONCLUSION: There has been significant recent progress in our understanding of the mechanisms underlying virus-induced airway inflammation in asthma and these advances will underpin the development of future clinical therapies.
11 citations
Cites background from "Impaired innate interferon inductio..."
...This IFN deficiency is also seen in severe therapy resistant asthmatic children, whose BECs (compared to controls) exhibit a higher viral load that negatively correlates with IFN-β and IFN-λ mRNA levels (31)....
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TL;DR: Alt exposure alters the airway epithelial immunity to viral infection by shifting toward more inflammatory but less antiviral responses, and Mechanistic studies suggested the positive role of NF-κB and mitogen-activated protein kinase pathways in the synergism and the attenuation of the TBK1-IRF3 pathway in the inhibition of IFN production.
Abstract: Multiple pathogens, such as bacteria, fungi, and viruses, have been frequently found in asthmatic airways and are associated with the pathogenesis and exacerbation of asthma Among these pathogens, Alternaria alternata (Alt), a universally present fungus, and human rhinovirus have been extensively studied However, their interactions have not been investigated In the present study, we tested the effect of Alt exposure on virus-induced airway epithelial immunity using live virus and a synthetic viral mimicker, double-stranded RNA (dsRNA) Alt treatment was found to significantly enhance the production of proinflammatory cytokines (eg, IL-6 and IL-8) induced by virus infection or dsRNA treatment In contrast to this synergistic effect, Alt significantly repressed type I and type III IFN production, and this impairment led to elevated viral replication Mechanistic studies suggested the positive role of NF-κB and mitogen-activated protein kinase pathways in the synergism and the attenuation of the TBK1-IRF3 pathway in the inhibition of IFN production These opposite effects are caused by separate fungal components Protease-dependent and -independent mechanisms appear to be involved Thus, Alt exposure alters the airway epithelial immunity to viral infection by shifting toward more inflammatory but less antiviral responses
10 citations
TL;DR: AIT effectively reduced the risk of exacerbations and lower respiratory tract infections in both seasonal- and perennial allergic asthma, suggesting that perennial allergy is seemingly not a stronger risk factor for respiratory infections and exacerbations than is seasonal allergy.
Abstract: Background Allergic asthma is associated with increased risk of respiratory tract infections and exacerbations. It remains unclear whether this susceptibility is conditioned by seasonal or by perennial allergy. Aim To investigate perennial allergy compared with seasonal allergy as a risk factor for lower respiratory tract infections and exacerbations in asthma and whether this risk can be reduced by allergen immunotherapy (AIT). Methodology This is a prospective register-based nationwide study of 18–44-year-olds treated with AIT during 1995–2014. Based on the type of AIT and use of anti-asthmatic drugs, patients were subdivided into two groups: perennial allergic asthma (PAA) versus seasonal allergic asthma (SAA). Data on antibiotics against lower respiratory tract infections (LRTI) and oral corticosteroids for exacerbations were analysed before starting AIT (baseline) and 3 years after completing AIT (follow-up). Results We identified 2688 patients with asthma treated with AIT, of whom 1249 had PAA and 1439 had SAA. At baseline, patients with SAA had more exacerbations (23.8% versus 16.5%, p≤0.001), but there were no differences in LRTI. During the 3-year follow-up, we observed a highly significant reduction of exacerbations with an average decrease of 57% in PAA and 74% in SAA. In addition, we observed a significant reduction of LRTI in both PAA and SAA: 17% and 20% decrease, respectively. Conclusion AIT effectively reduced the risk of exacerbations and lower respiratory tract infections in both seasonal and perennial allergic asthma. Perennial allergy is seemingly not a stronger risk factor for respiratory infections and exacerbations than seasonal allergy. Allergen immunotherapy effectively reduced the risk of lower respiratory tract infections and exacerbations in both seasonal and perennial allergic asthma and is potentially an early intervention strategy https://bit.ly/3sBEd5J
10 citations
TL;DR: In this paper, the effect of MC proteases on bronchial epithelial morphology and function was investigated, and the most significant increases were found in cell motility, cellular speed and cell elongation compared to non-stimulated cells.
Abstract: Chronic respiratory diseases are often characterized by impaired epithelial function and remodeling. Mast cells (MCs) are known to home into the epithelium in respiratory diseases, but the MC-epithelial interactions remain less understood. Therefore, this study aimed to investigate the effect of MC proteases on bronchial epithelial morphology and function. Bronchial epithelial cells were stimulated with MC tryptase and/or chymase. Morphology and epithelial function were performed using cell tracking analysis and holographic live-cell imaging. Samples were also analyzed for motility-associated gene expression. Immunocytochemistry was performed to compare cytoskeletal arrangement. Stimulated cells showed strong alterations on gene, protein and functional levels in several parameters important for maintaining epithelial function. The most significant increases were found in cell motility, cellular speed and cell elongation compared to non-stimulated cells. Also, cell morphology was significantly altered in chymase treated compared to non-stimulated cells. In the current study, we show that MC proteases can induce cell migration and morphological and proliferative alterations in epithelial cells. Thus, our data imply that MC release of proteases may play a critical role in airway epithelial remodeling and disruption of epithelial function.
10 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