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. 2010 Jan;3(1):69-80.
doi: 10.1038/mi.2009.109. Epub 2009 Aug 26.

Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma

Y A Bochkov  1 , K M Hanson, S Keles, R A Brockman-Schneider, N N Jarjour, J E Gern
Affiliations

Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma

Y A Bochkov et al. Mucosal Immunol. 2010 Jan.

Abstract

Rhinovirus (RV) infections trigger asthma exacerbations. Genome-wide expression analysis of RV1A-infected primary bronchial epithelial cells from normal and asthmatic donors was performed to determine whether asthma is associated with a unique pattern of RV-induced gene expression. Virus replication rates were similar in cells from normal and asthmatic donors. Overall, RV downregulated 975 and upregulated 69 genes. Comparisons of transcriptional profiles generated from microarrays and confirmed by quantitative reverse transcription PCR and cluster analysis showed some up- and downregulated genes in asthma cells involved in immune responses (IL1B, IL1F9, IL24, and IFI44) and airway remodeling (LOXL2, MMP10, FN1). Notably, most of the asthma-related differences in RV-infected cells were also present in the cells before infection. These findings suggest that differences in RV-induced gene expression profiles of cells from normal and mild asthmatic subjects could affect the acute inflammatory response to RV, and subsequent airway repair and remodeling.

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Conflict of interest statement

DISCLOSURE

The authors declared no conflict of interest.

Figures

Figure 1
Figure 1
RV1A infection induces similar cytopathic effect and viral RNA yield in cells obtained from donors with asthma and normal donors. (a) Representative microphotographs (magnification ×100) of primary bronchial epithelial (PBE) cells from one normal donor (no. 13) and one patient with asthma (no. 18) taken just after virus attachment period (left panel) and 16 hours post infection (p.i.) with medium alone (middle panel) or medium containing 10 plaque-forming units (PFU) per cell RV1A (right panel). (b) Quantification of viral RNA in adherent cells and growth media (including floating cells) collected 16 h p.i. of PBE cell cultures. Media samples both after microarray and quantitative PCR validation experiments were summarized. Viral RNA for each graph was calculated from each well of a six-well plate. Horizontal bars indicate medians. HRV, human RV.
Figure 2
Figure 2
Patterns of gene expression in normal and asthmatic cells. (a) Area-proportional Venn diagrams showing up- and downregulated genes determined in asthma and normal group samples after rhinovirus (RV) infection. Changes in gene expression (greater than or equal to twofold, adjusted P<0.05) common to both groups are shown by overlapping areas. The diagrams were generated with an online tool available at http://www.venndiagram.tk/. (b) Clustering analysis of gene expression patterns. Genes (n=42) were selected based on differential expression in infected cells from asthma vs. normal group, and then expression intensity values of mock- and RV-infected samples were analyzed by hierarchical clustering of samples and genes. The gene expression patterns of asthma (A) and normal (N) samples clustered together for uninfected (M; mock), as well as RV-infected, cells. Clusters of asthma samples are shown in blue. Color bar represents fold changes (log2 scale) in expression for each gene compared with median. HRV, human RV.
Figure 3
Figure 3
Genes upregulated by rhinovirus (RV) infection: analysis by microarray vs. quantitative reverse transcription (qRT)-PCR. Seven target genes that were up-regulated in both RV-infected normal (N) and asthma (A) samples by microarray were analyzed in separate experiments using qRT-PCR. Expression levels in RV-infected cells were compared with those in mock-infected cells. Expression profiles were determined in six normal and five asthma samples.
Figure 4
Figure 4
Quantitative PCR analysis of genes differentially expressed in asthma. Genes that were induced (n = 8) or inhibited (n = 4) by rhinovirus (RV) infection, and also differentially expressed in asthma samples by microarray were analyzed in separate experiments using quantitative reverse transcription PCR. Expression values are 2−ΔCt values determined by relative quantification method. Each line represents the mean and standard deviation. *P<0.05; †P<0.1. HRV, human RV.
Figure 5
Figure 5
Expression of three secreted pro-inflammatory cytokines in cell culture supernatants. Three tested cytokines were significantly induced at 16 h after rhinovirus (RV) infection, both in normal and asthmatic primary bronchial epithelial (PBE) cells (P<0.05); differences between asthma and normal groups were not significant (P>0.05). Each line represents the mean and standard deviation. HRV, human RV.
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