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: The role of IL-15 deficiency in the pathogenesis of virus-induced asthma exacerbations and the role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease is studied.
Abstract: 1. Custovic A, Johnston SL, Pavord I, Gaga M, Fabbri L, Bel EH, et al. EAACI position statement on asthma exacerbations and severe asthma. Allergy 2013;68:1520–1531. 2. Seemungal T, Harper-Owen R, Bhowmik A, Moric I, Sanderson G, Message S, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1618–1623. 3. Johnston NW, Olsson M, Edsbäcker S, Gerhardsson de Verdier M, Gustafson P, McCrae C, et al. Colds as predictors of the onset and severity of COPD exacerbations. Int J Chron Obstruct Pulmon Dis 2017;12:839–848. 4. Mallia P, Webber J, Gill SK, Trujillo-Torralbo MB, Calderazzo MA, Finney L, et al. Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 2018; 142:815–823. 5. Molyneaux PL, Mallia P, Cox MJ, Footitt J, Willis-Owen SA, Homola D, et al. Outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:1224–1231. 6. Mallia P, Footitt J, Sotero R, Jepson A, Contoli M, Trujillo-Torralbo MB, et al. Rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:1117–1124. 7. Mallia P, Message SD, Gielen V, Contoli M, Gray K, Kebadze T, et al. Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation. Am J Respir Crit Care Med 2011;183:734–742. 8. Sykes A, Macintyre J, Edwards MR, Del Rosario A, Haas J, Gielen V, et al. Rhinovirus-induced interferon production is not deficient in well controlled asthma. Thorax 2014;69:240–246. 9. Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, LazaStanca V, et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med 2005; 201:937–947. 10. Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PA, Bartlett NW, et al. Role of deficient type III interferon-lambda production in asthma exacerbations. Nat Med 2006;12:1023–1026. 11. Sykes A, Edwards MR, Macintyre J, Del Rosario A, Bakhsoliani E, Trujillo-Torralbo MB, et al. Rhinovirus 16-induced IFN-a and IFN-b are deficient in bronchoalveolar lavage cells in asthmatic patients. J Allergy Clin Immunol 2012;129:1506–1514. 12. Laza-Stanca V, Message SD, Edwards MR, Parker HL, Zdrenghea MT, Kebadze T, et al. The role of IL-15 deficiency in the pathogenesis of virus-induced asthma exacerbations. PLoS Pathog 2011;7:e1002114. 13. Message SD, Laza-Stanca V, Mallia P, Parker HL, Zhu J, Kebadze T, et al. Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. Proc Natl Acad Sci USA 2008;105:13562– 13567. 14. Gill MA, Bajwa G, George TA, Dong CC, Dougherty II, Jiang N, et al. Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells. J Immunol 2010; 184:5999–6006. 15. Rupani H, Martinez-Nunez RT, Dennison P, Lau LC, Jayasekera N, Havelock T, et al. Toll-like receptor 7 is reduced in severe asthma and linked to an altered microRNA profile. Am J Respir Crit Care Med 2016;194:26–37. 16. Baraldo S, Contoli M, Bazzan E, Turato G, Padovani A, Marku B, et al. Deficient antiviral immune responses in childhood: distinct roles of atopy and asthma. J Allergy Clin Immunol 2012;130:1307–1314. 17. Durrani SR, Montville DJ, Pratt AS, Sahu S, DeVries MK, Rajamanickam V, et al. Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children. J Allergy Clin Immunol 2012;130:489–495. 18. Edwards MR, Regamey N, Vareille M, Kieninger E, Gupta A, Shoemark A, et al. Impaired innate interferon induction in severe therapy resistant atopic asthmatic children. Mucosal Immunol 2013;6: 797–806. 19. Altman MC, Gill MA, Whalen E, Babineau DC, Shao B, Liu AH, et al. Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children. Nat Immunol 2019;20:637–651. 20. Hsu AC, Parsons K, Moheimani F, Knight DA, Hansbro PM, Fujita T, et al. Impaired antiviral stress granule and IFN-b enhanceosome formation enhances susceptibility to influenza infection in chronic obstructive pulmonary disease epithelium. Am J Respir Cell Mol Biol 2016;55:117–127. 21. Footitt J, Mallia P, Durham AL, Ho WE, Trujillo-Torralbo MB, Telcian AG, et al. Oxidative and nitrosative stress and histone deacetylase-2 activity in exacerbations of COPD. Chest 2016;149:62–73. 22. Djukanović R, Harrison T, Johnston SL, Gabbay F, Wark P, Thomson NC, et al.; INTERCIA Study Group. The effect of inhaled IFN-b on worsening of asthma symptoms caused by viral infections: a randomized trial. Am J Respir Crit Care Med 2014;190:145–154. 23. McCrae C, Olsson M, Aurell M, Lundin C, Paraskos J, Cavallin A, et al. On-demand inhaled interferon-beta 1a for the prevention of severa asthma exacerbations: results of the INEXAS phase 2a study [abstract]. Am J Respir Crit Care Med 2018;197:A6165. 24. Watson A, Spalluto CM, McCrae C, Cellura D, Burke H, Cunoosamy D, et al. Dynamics of IFN-b responses during respiratory viral infection: insights for therapeutic strategies. Am J Respir Crit Care Med 2020; 201:83–94.
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TL;DR: This review highlights key recent findings in asthma pathogenesis and virus-triggered asthma exacerbations; pDC biology and functionality; how pDC regulate the immune response; and pDC function in asthma.
Abstract: While medications are available to treat asthma symptoms and control inflammation, no treatments can cure asthma, and efforts to develop primary prevention strategies or improved exacerbation manag...
2 citations
TL;DR: Despite improvement in asthma maintenance treatment, exacerbations remain important issues and some studies have suggested that these episodes could be related to an alteration of innate immune defenses and particularly a defective production of type I and III interferons (IFN).
Abstract: Despite improvement in asthma maintenance treatment, exacerbations remain important issues. They are markers of severe asthma but can also occur in mild asthma (1). Viruses, and mainly Rhinoviruses (RVs), are the main triggers, and they may interact with aeroallergen-specific immunoinflammatory pathways in atopic patients (2,3). Some studies have suggested that these episodes could be related to an alteration of innate immune defenses and particularly a defective production of type I and III interferons (IFN) (4).
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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