Type-1 Interferon and Th2-Type Gene Expression Responses and Childhood Asthma

Several studies have demonstrated that type-1 interferons (T1-IFN)s suppress Th2-type (T2) inflammation in vitro. Both pathways play important roles in asthma pathogenesis; however, their relationship in vivo is unknown. We investigated upper airway gene expression in children with asthma during disease stability, upper respiratory infections (URI)s, and asthma exacerbations to define the relationship between these pathways. 165 children with exacerbation-prone asthma in the Inner City Asthma Consortium MUPPITS1 cohort had nasal lavage sampling at baseline and during a one-week period following onset of URI symptoms with or without resultant asthma exacerbations. Gene expression was assessed by RNA-sequencing and modular analysis of T1-IFN (including STAT1, STAT2, IRF7) and T2 (including IL4, IL5, IL13) response gene modules, and virus infection by quantitative PCR. There was a significant non-linear association between T1-IFN and T2 response gene expression modules (quadratic model: p<1E-10, r2=0.23), which demonstrated an inverse association between the pathways at moderate T1-IFN expression levels, but a positive association at high levels. The positive association was seen predominantly in rhinovirus-positive URIs and asthma exacerbations. Furthermore, rhinovirus load was significantly correlated with T1-IFN module expression (p=1.25E-9, R=0.47). In children with asthma, at high levels of T1-IFN response, T1-IFN gene expression was unexpectedly positively associated with T2 gene expression. This was most pronounced in children with rhinovirus infections. The results suggest that while negative feedback may normally exist between the two pathways, there can be an uncoupling of this negative feedback in the airway of children with asthma during respiratory illnesses.