Impaired type I interferon regulation in the blood transcriptome of recurrent asthma exacerbations

Jose L. Gomez, Maria P. Diaz, Gustavo Nino, Clemente J. Britto

Asthma exacerbations are an important cause of morbidity in asthma. Respiratory infections are often involved in asthma exacerbations in both children and adults. Some individuals with asthma have increased susceptibility to viral infections and as a result increased rates of asthma exacerbations. We sought to identify a transcriptomic signature in the blood associated with asthma exacerbations triggered by respiratory infections (AETRI) and determine its association with increased risk for asthma exacerbations. We conducted a two-step study using publicly available, previously generated transcriptomic signatures in peripheral blood mononuclear cells (PBMCs) from asthmatics to identify novel markers of increased risk for asthma exacerbations. In the 1st step, we identified an in vitro PBMC signature in response to rhinovirus. In the 2nd step, we used the in vitro signature to filter PBMC transcripts in response to asthma exacerbations in an independent in vivo cohort. Three different subgroups were identified and studied in the in vivo cohort: 1. Single AETRI; 2. Multiple AETRIs; and 3. Single non-infectious asthma exacerbations. We performed pathway and network analyses in all independent comparisons. We also performed an immunologic gene set enrichment analysis (GSEA) of the comparison between single AETRI and non-infectious asthma exacerbations. The in vitro signature identified 4354 differentially expressed genes (DEGs) with a fold change (FC) ≥ 1.2, false discovery rate (FDR) < 0.05. Subsequent analyses filtered by this in vitro signature on an independent cohort of adult asthma identified 238 DEGs (FC≥1.1, FDR < 0.1) in subjects with a single AETRI and no DEGs in single non-infectious asthma exacerbations. A comparison between the response in subjects with single and multiple AETRIs identified two discordant gene subsets. In the largest discordant subset (n = 63 genes) we identified an impaired type I interferon and STAT1 response in multiple AETRIs during the acute phase of the exacerbation and an upregulated STAT1 response at baseline. The STAT1 upregulation at baseline in subjects with multiple AETRIs was accompanied by upregulation of pro-inflammatory molecules including IL-15, interferon-stimulated genes (ISGs), several toll-like receptors 2, - 4, - 5 and - 8 and a triggering receptor expressed on myeloid cells 1 (TREM1) network. Subjects with asthma and multiple AETRIs display a pro-inflammatory signature at baseline, associated with elevated STAT, IL-15 and ISGs, and an impaired STAT1 response during acute asthma exacerbations.