Persistent activation of interlinked Th2-airway epithelial gene networks in sputum-derived cells from aeroallergen-sensitized symptomatic atopic asthmatics

Abstract

RationaleAtopic asthma is a persistent disease characterized by intermittent wheeze and progressive loss of lung function. The disease is thought to be driven primarily by chronic aeroallergen-induced Th2-associated airways inflammation. However, the vast majority of atopics do not develop asthma-related wheeze, despite ongoing exposure to aeroallergens to which they are strongly sensitized, indicating that additional pathogenic mechanism(s) operate in conjunction with Th2 immunity to drive asthma pathogenesis.\n\nObjectivesEmploy systems level analyses to identify inflammation-associated gene networks operative at baseline in sputum-derived RNA from house dust mite-sensitized (HDMs) subjects with/without wheezing history; identify networks characteristic of the ongoing asthmatic state. All subjects resided in the constitutively-HDMhigh Perth environment.\n\nMethodsGenome wide expression profiling by RNASeq followed by gene coexpression network analysis.\n\nMeasurements/ResultsHDMs-nonwheezers displayed baseline gene expression in sputum including IL-5, IL-13 and CCL17. HDMs-wheezers showed equivalent expression of these classical Th2-effector genes but their overall baseline sputum signatures were more complex, comprising hundreds of Th2-associated and epithelial-associated genes, networked into two separate coexpression modules. The first module was connected by the hubs EGFR, ERBB2, CDH1 and IL-13. The second module was associated with CDHR3, and contained genes that control mucociliary clearance.\n\nConclusionsOur findings provide new insight into the inflammatory mechanisms operative at baseline in the airway mucosal microenvironment in atopic asthmatics undergoing natural perennial aeroallergen exposure. The molecular mechanism(s) that determine susceptibility to asthma amongst these subjects involve interactions between Th2-and epithelial function-associated genes within a complex co-expression network, which is not operative in equivalently sensitized/exposed atopic non-asthmatics.\n\nFundingThis study was funded by the Asthma Foundation WA, the Department of Health WA, and the NHMRC. AB is funded by a BrightSpark Foundation McCusker Fellowship. GLH is a NHMRC Fellow. AG is supported by the McCusker Charitable Foundation Bioinformatics Centre. ACJ is a recipient of an Australian Postgraduate Award and a Top-Up Award from the University of Western Australia.