Gene expression in the brain during reovirus encephalitis

Abstract

Viral encephalitis remains a significant cause of morbidity and mortality throughout the world. We performed microarray analysis to identify genes and pathways that are differentially regulated during reovirus encephalitis and that may provide novel therapeutic targets for virus-induced diseases of the central nervous system (CNS). An increase in the expression of 130 cellular genes was found in the brains of reovirus-infected mice at early times post infection, compared to mock-infected controls. The up-regulation of these genes was consistent with activation of innate immune responses, particularly interferon signaling. At later times post infection, when significant CNS injury is present and mice exhibit signs of severe neurologic disease, many more (1374) genes were up-regulated, indicating that increased gene expression correlates with disease pathology. Virus-induced gene expression at late times post infection was again consistent with the activation of innate immune responses. However, additional significant pathways included those associated with cytokine signaling and apoptosis, both of which can contribute to CNS injury. This is the first report comparing virus-induced cellular gene and pathway regulation at early and late times following virus infection of the brain. The shift of virus-induced gene expression from innate immune responses at early times post infection to cytokine signaling and apoptosis at later times suggests a potential therapeutic strategy that preserves early protective responses whilst inhibiting later responses that contribute to pathogenesis.

Daxx Upregulation within the Cytoplasm of Reovirus-Infected Cells Is Mediated by Interferon and Contributes to Apoptosis

“…1a). The magnitude of Daxx transcript upregulation at 8 days post-T3A infection (5.2-fold over mock; P ϭ 0.003) was comparable to that previously seen 8 days post-T3D infection (4.1-fold over mock; P ϭ 0.000059) by microarray analysis (44).…”

“…Upregulation of Daxx was previously reported in bone marrow cells following type I IFN exposure (46,47). We previously showed that interferon signaling is initiated in the reovirus-infected brain and serves to limit local viral tropism and systemic viral spread (11,40,44). Thus, we hypothesized that IFN was driving Daxx upregulation during reovirus infection.…”

“…Oligonucleotide microarray analysis led to the identification of Daxx as a cellular gene that was increased in expression within the brains of mice infected with T3D (44). To confirm this observation and determine the kinetics of reovirus-elicited Daxx upregulation, 2-day-old Swiss Webster mice were inoculated i.c.…”

Death Receptor-Mediated Apoptotic Signaling Is Activated in the Brain following Infection with West Nile Virus in the Absence of a Peripheral Immune Response

“…For example, (i) Daxx is upregulated in the spleens of mice infected with neuroinvasive strains of WNV compared to noninvasive strains (23); (ii) the death receptor-associated genes encoding cIAP2, TRAIL, TNF, and TRAF1 are upregulated in WNV-infected human retinal pigment epithelium (24), and (iii) multiple pathways involved in apoptosis, including induction of apoptosis by HIV-1, were identified in the brains of horses with exposure to WNV (25). In addition, we previously performed microarray analysis on RNA extracted from the brains of reovirus-infected mice (26). The expression of all DR-associated WNV-induced genes with an expression change of Ն2 was also significantly changed following infection of the brain with reovirus (not shown), including the gene encoding Daxx (27), suggesting that similar patterns of gene expression are seen in the brain following infection with a variety of viruses.…”

Mitochondrial p53 Contributes to Reovirus-Induced Neuronal Apoptosis and Central Nervous System Injury in a Mouse Model of Viral Encephalitis

“…Increased levels of p53 have been shown to promote cell death by transcriptionally activating proapoptotic genes, including Bax and PUMA. Our prior microarray studies indicated that Bax and PUMA are not upregulated in the brain throughout the course of reovirus infection (21), suggesting that the transcriptional activity of p53 does not contribute to pathology during reovirus encephalitis. The cytoplasmic location of p53 ( Fig.…”