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Contrasting gene expression patterns associated with high and low rhinovirus stimulated IFN-α production

ABSTRACT: Introduction: Viral respiratory infections cause considerable morbidity and economic loss. While rhinoviruses (RV) typically cause little more than the common cold, they can produce severe infections and disease exacerbations in susceptible individuals, including those with chronic lung diseases. Variations in the regulation of key antiviral cytokines, particularly type I interferon (IFN-α and IFN-b), may contribute to RV susceptibility, but are not well understood. Method: Whole genome transcription patterns were assessed in samples from 74 individuals demonstrating high or low IFN-α production following RV stimulation in vitro. Results: In unstimulated samples (baseline) the high IFN-α producer group showed higher expression of genes associated with plasmacytoid dendritic cells, the complement system, B-cell chemokines, immune regulation, macrophages, and vitamin D activation and lower expression of genes linked to haemoglobin and haem biosynthesis, wound healing, stress response and pro-inflammatory genes than the low IFN-α producer group. After RV stimulation, the high IFN-α producer group showed more intense upregulation of diverse immune function genes including IFNs and greater downregulation of genes linked to structural and extra-cellular matrix functions than the low IFN-α producer group. Patterns of antibacterial gene expression varied between groups. Healthy people and those with asthma generally showed similar gene expression patterns. These findings highlight multiple biological pathways whose expression patterns differ substantially between high and low IFN-α producers. These differences likely contribute to variations in anti-RV immunity and immunopathology between individuals.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166292 | GEO | 2021/07/31

REPOSITORIES: GEO

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Project description:Interferon (IFN)-alpha causes high rates of depression and fatigue, and is used to investigate the impact of innate immune cytokines on brain and behavior. However, little is known about transcriptional profiles of circulating immune cells during chronic IFN-alpha administration. Accordingly, genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells from 21 patients with chronic hepatitis C virus either awaiting IFN-alpha therapy (n=10) or after 12 weeks of IFN-alpha treatment (n=11). Significance analysis of microarray data identified 252 up-regulated gene transcripts, the majority of which were related to IFN-alpha/antiviral or innate-immune/inflammatory signaling. Of these upregulated genes, 2'-5'-oligoadenylate synthetase 2 (OAS2) was the only gene that was differentially expressed in patients that developed IFN-alpha-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks of IFN-alpha administration. Promoter-based bioinformatic and cellular origin analyses revealed IFN-alpha-induced increases in genes bearing transcription factor binding motifs (TFBMs) related to myeloid differentiation, IFN-alpha signaling, API and CREB/ATF family of transcription pathways, with changes derived primarily from monocytes and plasmacytoid dendritic cells. Patients with high depression/fatigue scores demonstrated up-regulation of genes bearing TFBMs for myeloid differentiation, IFN-alpha and AP1 signaling, and down regulation of TFBMs for CREB/ATF-related transcription factors. Cellular origin analyses indicated a shift toward genes derived from CD8+T and NK cells in subjects with high depression/fatigue scores. These results reveal an antiviral and inflammatory transcriptional profile after 12 weeks IFN-alpha, accompanied by increased OAS2 expression, decreased CREB/ATF transcriptional control, and a shift from monocyte-derived genes to those of cytotoxic lymphocytes in IFN-alpha-induced depression/fatigue. Total RNA was isolated from the peripheral blood mononuclear cells (PBMC) obtained at 12 weeks from HCV patients treated with IFN-alpha plus ribavirin (n=11) and untreated HCV patients awaiting IFN-alpha/ribavirin therapy (control subjects, n=10).

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Contrasting gene expression patterns associated with high and low rhinovirus stimulated IFN-α production

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