Asthmatics with exacerbation during acute respiratory illness exhibit unique transcriptional signatures within the nasal mucosa

Abstract

BackgroundAcute respiratory illness is the leading cause of asthma exacerbations yet the mechanisms underlying this association remain unclear. To address the deficiencies in our understanding of the molecular events characterizing acute respiratory illness-induced asthma exacerbations, we undertook a transcriptional profiling study of the nasal mucosa over the course of acute respiratory illness amongst individuals with a history of asthma, allergic rhinitis and no underlying respiratory disease.MethodsTranscriptional profiling experiments were performed using the Agilent Whole Human Genome 4X44K array platform. Time point-based microarray and principal component analyses were conducted to identify and distinguish acute respiratory illness-associated transcriptional profiles over the course of our study. Gene enrichment analysis was conducted to identify biological processes over-represented within each acute respiratory illness-associated profile, and gene expression was subsequently confirmed by quantitative polymerase chain reaction.ResultsWe found that acute respiratory illness is characterized by dynamic, time-specific transcriptional profiles whose magnitudes of expression are influenced by underlying respiratory disease and the mucosal repair signature evoked during acute respiratory illness. Most strikingly, we report that people with asthma who experience acute respiratory illness-induced exacerbations are characterized by a reduced but prolonged inflammatory immune response, inadequate activation of mucosal repair, and the expression of a newly described exacerbation-specific transcriptional signature.ConclusionFindings from our study represent a significant contribution towards clarifying the complex molecular interactions that typify acute respiratory illness-induced asthma exacerbations.

Pathobiology of Severe Asthma

“…Some studies have suggested that airway epithelial cells from asthmatic patients have a deficiency in innate responses, particularly in Type-I and Type-III interferons, which could promote adaptive immune responses that lead to asthma exacerbations (121,122). Similarly, ILC2 cells are innate-responding, non-CD4-expressing cells that can enhance expression of Type-2 cytokines (see above).…”

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

“…However, these studies focused on expression changes during acute exacerbations and provided no information regarding expression across the broad range of asthma control states that precede exacerbation. Given that cellular and transcriptional responses during acute asthma exacerbation are highly complex (6), the gene pathways perturbed may be quite different from those that destabilize asthma control and trigger exacerbation in the days preceding an acute crisis. Although detection of these earlier alterations may be more informative for the development of preventative controller strategies (7), only one small study of differential gene expression and asthma control has been conducted in circulating leukocytes from children in a broadly uncontrolled severe or controlled persistent disease state (8).…”

“…Using clinical phenotype data available in Asthma BRIDGE and in CAMP, we developed two composite scores summarizing self-reported asthma control in the preceding 6 months (chronic, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and 7 days (acute, 0-28), respectively, each modeled on the ACT questionnaire (11), where higher scores indicate worse asthma control. Based on the medians of the corresponding phenotypic distributions, optimal chronic asthma control was defined as a score less than or equal to six in BRIDGE WB and moderately suboptimal asthma control was defined as a score less than or equal to 11 in BRIDGE CD4 ( Figure 2).…”

Shift and adapt: the costs and benefits of karyotype variations

“…Candida albicans , long considered an obligate diploid, recently was found to generate haploids following passage through a mouse model, and following exposure to the antifungal drug fluconazole [3,4]. Similarly, rare tetraploids have been sampled from clinical isolates of C. albicans [5,6], and polyploid "titan" cells were recently identified in the typically-haploid basidiomycete Cryptococcus neoformans [7,8] (reviewed in [9]). Aneuploid variants also have been documented at appreciable frequencies in many fungal taxa in a diversity of circumstances: within the S. cerevisiae deletion collection constructed by transformation [10], following drug stress in C. albicans [11] and C. neoformans [12], in meiotic spores of C. lusitaniae [13] and through unisexual mating in C. neoformans [14].…”