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. 2014 Mar 11;5(2):e00902-14.
doi: 10.1128/mBio.00902-14.

Virus-induced transcriptional changes in the brain include the differential expression of genes associated with interferon, apoptosis, interleukin 17 receptor A, and glutamate signaling as well as flavivirus-specific upregulation of tRNA synthetases

Penny Clarke, J Smith Leser, Richard A Bowen, Kenneth L Tyler

Virus-induced transcriptional changes in the brain include the differential expression of genes associated with interferon, apoptosis, interleukin 17 receptor A, and glutamate signaling as well as flavivirus-specific upregulation of tRNA synthetases

Penny Clarke et al. mBio. .

Abstract

Flaviviruses, particularly Japanese encephalitis virus (JEV) and West Nile virus (WNV), are important causes of virus-induced central nervous system (CNS) disease in humans. We used microarray analysis to identify cellular genes that are differentially regulated following infection of the brain with JEV (P3) or WNV (New York 99). Gene expression data for these flaviviruses were compared to those obtained following infection of the brain with reovirus (type 3 Dearing), an unrelated neurotropic virus. We found that a large number of genes were up-regulated by all three viruses (using the criteria of a change of >2-fold and a P value of <0.001), including genes associated with interferon signaling, the immune system, inflammation, and cell death/survival signaling. In addition, genes associated with glutamate signaling were down-regulated in infections with all three viruses (criteria, a >2-fold change and a P value of <0.001). These genes may serve as broad-spectrum therapeutic targets for virus-induced CNS disease. A distinct set of genes were up-regulated following flavivirus infection but not following infection with reovirus. These genes were associated with tRNA charging and may serve as therapeutic targets for flavivirus-induced CNS disease. IMPORTANCE Viral infections of the central nervous system (CNS) are an important cause of morbidity and mortality. Treatment options for virus-induced CNS disease are limited, and for many clinically important neurotropic viruses, no specific therapy of proven benefit is currently available. We performed microarray analysis to identify genes that are differentially regulated in the brain following virus infection in order to identify pathways that might provide novel therapeutic targets for virus-induced CNS disease. Although several studies have described gene expression changes following virus infection of the brain, this report is the first to directly compare large-scale gene expression data from different viruses. We identified genes that are differentially regulated in infection of the brain with viruses from different families and those which appear to be specific to flavivirus infections.

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Figures

FIG 1
FIG 1
Virus infection of the brain causes changes in cellular gene expression. Mice were infected with JEV (40 PFU), WNV (100 PFU), or reovirus (1,000 PFU) by i.c. inoculation. At 5 to 8 days postinfection, when mice were showing clinical manifestations of encephalitis, brains were harvested and RNA was analyzed using Affymetrix gene chips. (A) Volcano plots showing gene expression changes in the brain following infection with JEV, WNV, and reovirus. Each dot represents one gene on the Affymetrix gene chip. Genes with changes in expression greater than 2-fold (P < 0.001) are indicated (larger dots). (B) Principal components analysis of microarray data. (C) Table showing the number of differentially expressed genes following infection with JEV, WNV, and reovirus. (D) Venn diagram showing the overlap of differentially expressed genes following virus infection of the brain. (E) Graph showing the number and fold change of up- and down-regulated genes (P < 0.001) following virus infection.
FIG 2
FIG 2
RT-PCR confirms differential gene expression identified by microarray. RT-PCR confirmation of select genes associated with inflammation (A) and cell death and survival signaling (B). The graphs show changes in expression (infected versus mock infected) following infection with WNV, as determined by RT-PCR and microarray analysis.
FIG 3
FIG 3
Ingenuity pathway analysis identifies cellular signaling pathways that are associated with genes that are up-regulated in infections with JEV, WNV, and reovirus. IPA was performed on genes that were differentially up-regulated following virus infection (change, >2-fold; P < 0.001). IPA identified genes involved in IFN signaling (A), death receptor signaling (B), and IL-17RA signaling (C) as being common to infections with JEV, WNV, and reovirus. The charts are adapted from IPA results. Shaded boxes represent genes that were differentially up-regulated following virus infection.
FIG 4
FIG 4
Interferon-regulated genes are up-regulated in the brain following virus infection. The Interferome database was used to identify IFN-regulated genes that were up-regulated in the brain following infection with JEV, WNV, or reovirus. Pie charts were generated showing the number of IFN-regulated genes that were differentially up-regulated following infection with all 3 viruses, 2 of the 3 viruses, and individual viruses (A) and the number of IFN-regulated genes that were up-regulated to a higher degree following reovirus infection than following infection with JEV or WNV (B).
FIG 5
FIG 5
RT-PCR confirmation of microarray data, showing that glutamate signaling and tRNA charging are associated with genes that are differentially expressed in the brain following virus infection. The graphs show RT-PCR confirmation of glutamate signaling genes that were shown by microarray analysis to be down-regulated following infection with JEV, WNV, and reovirus (A) and of tRNA synthetases that were shown by microarray analysis to be up-regulated following infection with JEV and WNV (B). RT-PCR was performed on virus-infected (n = 3) and mock-infected (n = 3) mice that were independent from those used for the microarray experiments. Columns represent average expression values. Error bars represent standard errors of the mean.
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