Rhinovirus infection results in stronger and more persistent genomic dysregulation: Evidence for altered innate immune response in asthmatics at baseline, early in infection, and during convalescence

Abstract

BackgroundRhinovirus (HRV) is associated with the large majority of virus-induced asthma exacerbations in children and young adults, but the mechanisms remain poorly defined.MethodsAsthmatics and non-asthmatic controls were inoculated with HRV-A16, and nasal epithelial samples were obtained 7 days before, 36 hours after, and 7 days after viral inoculation. RNA was extracted and subjected to RNA-seq analysis.ResultsAt baseline, 57 genes were differentially expressed between asthmatics and controls, and the asthmatics had decreased expression of viral replication inhibitors and increased expression of genes involved in inflammation. At 36 hours (before the emergence of peak symptoms), 1329 genes were significantly altered from baseline in the asthmatics compared to 62 genes in the controls. At this time point, asthmatics lacked an increase in IL-10 signaling observed in the controls. At 7 days following HRV inoculation, 222 genes were significantly dysregulated in the asthmatics, whereas only 4 genes were dysregulated among controls. At this time point, the controls but not asthmatics demonstrated upregulation of SPINK5.ConclusionsAs judged by the magnitude and persistence of dysregulated genes, asthmatics have a substantially different host response to HRV-A16 infection compared with non-asthmatic controls. Gene expression differences illuminate biologically plausible mechanisms that contribute to a better understanding of the pathogenesis of HRV-induced asthma exacerbations.

T cells in severe childhood asthma

“…These data suggest that the inflamed airways of allergic asthmatics contribute to dysregulated anti‐viral responses and that this effect is reversed by anti‐IgE treatment. In agreement with this notion, HRV was found to induce Th2‐promoting cytokines in cultured bronchial epithelial cells from patients with severe or allergic asthma, and experimental infection induced the expression of many more genes in nasal epithelial cells of asthmatics compared with controls . Similarly, levels of TSLP or IL‐33 were elevated in the airways of young asthmatic children and adult patients infected with HRV .…”

Environmental exposures and mechanisms in allergy and asthma development

“…Mechanisms of viral-induced wheezing. Transcriptomic analysis comparing asthmatics with nonasthmatic controls following infection with HRV demonstrated increased magnitude and persistence of epithelial gene dysregulation throughout the course of infection (78). Distinct differences in the quality of the response following HRV infection were observed in asthmatics, including increased expression of genes involved in inflammation, decreased expression of viral replication inhibitors, and impaired induction of the (50,51).…”

“…Viral infections in wheezing and asthma development. Early-life acute respiratory tract infections (ARIs) are strongly associated with wheeze in infants and asthma inception and exacerbation in children; however, it is still debated whether they are causative in the pathogenesis of asthma or whether they unmask asthma jci.org Volume 129 Number 4 April 2019 serine protease inhibitor SPINK5, which has been implicated in epithelial maintenance and repair (78). Patients with asthma also displayed increased upper and lower respiratory symptoms, markedly higher viral load, and higher nasal Th2 cytokine levels (68).…”

Role of early life immune regulation in asthma development

“…While viral infections shift the immune response to the Th2 side, anti-viral response carried out by mediators of the Th1 axis is reduced [34,115]. Moreover, dysregulation of epithelial gene expression increased inflammation, and decreased inhibition of viral replication was shown [116].…”