Atopic asthma after rhinovirus-induced wheezing is associated with DNA methylation change in the SMAD3 gene promoter.
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ABSTRACT:
SUBMITTER: Lund RJ
PROVIDER: S-EPMC6055882 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
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Atopic asthma after rhinovirus-induced wheezing is associated with DNA methylation change in the SMAD3 gene promoter.
Lund R J RJ Osmala M M Malonzo M M Lukkarinen M M Leino A A Salmi J J Vuorikoski S S Turunen R R Vuorinen T T Akdis C C Lähdesmäki H H Lahesmaa R R Jartti T T
Allergy 20180521 8
Children with rhinovirus-induced severe early wheezing have an increased risk of developing asthma later in life. The exact molecular mechanisms for this association are still mostly unknown. To identify potential changes in the transcriptional and epigenetic regulation in rhinovirus-associated atopic or nonatopic asthma, we analyzed a cohort of 5-year-old children (n = 45) according to the virus etiology of the first severe wheezing episode at the mean age of 13 months and to 5-year asthma outc ...[more]
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Project description:BackgroundPersistent childhood asthma is mainly atopy driven. However, limited data exist on the risk factors for childhood asthma phenotypes.ObjectiveWe sought to identify risk factors at the first severe wheezing episode for current asthma 7 years later and separately for atopic and nonatopic asthma.MethodsOne hundred twenty-seven steroid-naive children with the first severe wheezing episode (90% hospitalized/10% emergency department treated) were followed for 7 years. The primary outcome was current asthma at age 8 years, which was also analyzed separately as atopic and nonatopic asthma. Risk factors, including sensitization, viral cause, and other main asthma risk factors, were analyzed.ResultsAt study entry, median age was 11 months (interquartile range, 6-16 months); 17% were sensitized, and 98% were virus positive. Current asthma (n = 37) at 8 years was divided into atopic (n = 19) and nonatopic (n = 18) asthma. The risk factors for current atopic asthma at study entry were sensitization (adjusted odds ratio [OR], 12; P < .001), eczema (adjusted OR, 4.8; P = .014), and wheezing with rhinovirus (adjusted OR, 5.0; P = .035). The risk factors for nonatopic asthma were the first severe respiratory syncytial virus/rhinovirus-negative wheezing episode (adjusted OR, 8.0; P = .001), first wheezing episode at age less than 12 months (adjusted OR, 7.3; P = .007), and parental smoking (adjusted OR, 3.8; P = .028).ConclusionsThe data suggest diverse asthma phenotypes and mechanisms that can be predicted by using simple clinical markers at the time of the first severe wheezing episode. These findings are important for designing early intervention strategies for secondary prevention of asthma.
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Project description:Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.
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