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. 2012 Nov;64(11):3553-63.
doi: 10.1002/art.34631.

Gene profiling of Chikungunya virus arthritis in a mouse model reveals significant overlap with rheumatoid arthritis

Affiliations

Gene profiling of Chikungunya virus arthritis in a mouse model reveals significant overlap with rheumatoid arthritis

Helder I Nakaya et al. Arthritis Rheum. 2012 Nov.

Abstract

Objective: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes a chronic debilitating polyarthralgia/polyarthritis, for which current treatments are often inadequate. To assess whether new drugs being developed for rheumatoid arthritis (RA) might find utility in the treatment of alphaviral arthritides, we sought to determine whether the inflammatory gene expression signature of CHIKV arthritis shows any similarities with RA or collagen-induced arthritis (CIA), a mouse model of RA.

Methods: Using a recently developed animal model of CHIKV arthritis in adult wild-type mice, we generated a consensus CHIKV arthritis gene expression signature, which was used to interrogate publicly available microarray studies of RA and CIA. Pathway analyses were then performed using the overlapping gene signatures.

Results: Gene set enrichment analysis showed that there was a highly significant overlap in the differentially expressed genes in the CHIKV arthritis model and in RA. This concordance also increased with the severity of RA, as measured by the inflammation score. A highly significant overlap was also seen between CHIKV arthritis and CIA. Pathway analysis revealed that the overlap between these arthritides was spread over a range of different inflammatory processes. Involvement of T cells and interferon-γ (IFNγ) in CHIKV arthritis was confirmed in studies of MHCII-deficient mice and IFNγ-deficient mice, respectively.

Conclusion: These results suggest that RA, a chronic autoimmune arthritis, and CHIKV disease, usually a self-limiting viral arthropathy, share multiple inflammatory processes. New drugs and biologic therapies being developed for RA may thus find application in the treatment of alphaviral arthritides.

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Figures

Figure 1
Figure 1
Global gene expression changes induced by chikungunya virus (CHIKV) infection. A, Unsupervised principal components analysis (PCA) was used to assess clustering of expression data obtained from feet of mice days (d) 0.25, 1, 3, and 7 after infection with Reunion Island or Asian CHIKV isolates, feet of mock-infected mice, and feet of uninfected control mice. Expression data from all 28,310 annotated probe sets were used for this analysis. B, Pathways that were significantly enriched with differentially expressed genes in Reunion Island CHIKV-infected and Asian CHIKV-infected feet were identified. Values in boxes are the numbers of up- or down-regulated genes in each pathway at each time point. The total number of up- or down-regulated genes is shown in bold in parentheses. Pathways were obtained from the Gene Ontology and Ingenuity databases; the total number of genes in each pathway is given in parentheses next to the pathway description. C, Temporal expression patterns of the same pathways shown in B. Lines show the mean fold-change in expression of genes within each pathway for both CHIKV isolates at each time point. The number of genes used to determine the means is shown in parentheses. Asterisks indicate statistically significant difference (paired t-test P value <0.001 using all the genes in parentheses) between the Reunion Island CHIKV-infected and Asian CHIKV-infected feet. NK = natural killer; IFN = interferon.
Figure 2
Figure 2
Comparison of differentially expressed genes in Asian chikungunya virus (CHIKV)–infected and Reunion Island CHIKV-infected feet. The number of differentially expressed genes in Reunion Island CHIKV-infected feet at each time point postinfection is shown in black plus blue bars. The white outlined bars represent the number of these genes that were also differentially expressed in Asian CHIKV-infected feet at the same time point. The black bars represent the number of genes that were differentially expressed in Reunion Island CHIKV-infected feet at the indicated time point that were also differentially expressed in Asian CHIKV-infected feet at ANY time point (Shared). The blue bars represent the number of genes that were uniquely differentially expressed in Reunion Island CHIKV-infected feet at the indicated time point (Unique). The numbers above the bars represent the mean ± SD fold change in gene expression in Reunion Island CHIKV-infected feet for unique (blue) or shared (black) genes. For probe sets that represent the same gene, the highest differential expression value was used for this calculation. Cutoff values for up-regulation on days 0.25, 1, 3, and 7 postinfection were 1.7, 1.5, 1.5, and 1.6, respectively, in the Reunion Island isolates and 1.7, 1.5, 1.4, and 1.6, respectively, in the Asian isolates, while cutoff values for down-regulation at these time points were 1.7, 1.5, 1.5, and 1.6, respectively, in the Reunion Island isolates and 1.7, 1.5, 1.4, and 1.6, respectively, in the Asian isolates.
Figure 3
Figure 3
Comparison of chikungunya virus (CHIKV) arthritis and rheumatoid arthritis (RA) gene signatures. A, GSEA analysis showing a statistically significant enrichment of up- (left panel, 282 genes in "core enrichment" out of 465 genes) and down- (right panel, 68 genes in "core enrichment" of 187 genes) regulated genes from CHIKV arthritis in the up- and down-regulated genes, respectively, identified in RA (22). The CHIKV arthritis genes (Figure 2, black bars, day 7) are listed in Supplementary Table 1, on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131 (22). B, A heatmap showing the relative expression levels of the 282 up-regulated genes in the CHIKV arthritis gene set that were enriched in RA patients. Columns represent the 5 control, and 5 RA samples in the study (22) and their respective inflammation scores. The 282 genes are listed in Supplemental Table 2. C, Positive correlation between "Distance to health" and inflammation scores. The "Distance to health" (black bars) was calculated as described (30). Briefly, the number of standard deviations from the mean expression of healthy samples was determined for each of the 282 genes in B. The score was calculated by summing these standard deviations (where SD from the mean > 2) of all 282 genes. The box outlined in blue (left) shows the Pearson’s correlation and significance of the association (by 1-tailed t-test). FDR = false discovery rate.
Figure 4
Figure 4
Comparison of chikungunya virus (CHIKV) arthritis and mouse collagen-induced arthritis (CIA) gene signatures. GSEA analysis showing a statistically significant enrichment of up- (left panel, 437 genes in "core enrichment" out of 751 genes) and down- (right panel, 173 genes in "core enrichment" out of 328 genes) regulated genes from CHIKV arthritis in the up- and down-regulated genes, respectively, identified in CIA (23). The CHIKV arthritis gene sets were the same as those used in Figure 3. FDR = false discovery rate.
Figure 5
Figure 5
Gene pathway analyses, and role of T cells and cytokines in chikungunya virus (CHIKV) arthritis. A, Ingenuity Pathway Analysis of the 282 up-regulated genes identified by GSEA (core enrichment) in Figure 3A (CHIKV and rheumatoid arthritis [RA]) (left panel) and Ingenuity Pathway Analysis of the 437 up-regulated genes identified by GSEA (core enrichment) in Figure 4 (CHIKV and collagen-induced arthritis [CIA]) (right panel). The canonical pathways identified are grouped into themes, and the log(P value) is plotted for each pathway. As individual genes can appear in multiple pathways, the total number of unique genes within each theme is shown to the right of the bars. Of the 101 genes in the "Other" pathway for RA, all but 22 are present in the preceding themes. Of the 106 genes in the "Other" pathway for CIA, all but 26 are present in the preceding themes. The pathways and the genes are listed in Supplementary Table 2, on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131. B, A reduction in foot swelling is seen in mice deficient in MHCII (MHCII Δ/Δ) and mice deficient in interferon-γ (IFNγ–/–). Wild-type, MHCII Δ/Δ, and IFNγ–/– mice were infected with CHIKV, and foot swelling was measured at various time points after infection. In wild-type mice, histologically confirmed arthritis peaks on days 6/7 postinfection, which manifests as readily measurable foot swelling (10). Bars show the mean ± SEM. P < 0.001 for wild-type mice (n = 14–30 feet) versus MHCII Δ/Δ mice (n = 20 feet) on days 6 and 7, by t-test; P = 0.011 on day 6 and P = 0.003 on day 7 for wild-type versus IFNγ–/– mice (each n = 10 feet), by t-test.

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