Transcriptome Signature of Virulent and Attenuated Pseudorabies Virus-Infected Rodent Brain

Abstract

Mammalian alphaherpesviruses normally establish latent infections in ganglia of the peripheral nervous system in their natural hosts. Occasionally, however, these viruses spread to the central nervous system (CNS), where they cause damaging, often fatal, infections. Attenuated alphaherpesvirus derivatives have been used extensively as neuronal circuit tracers in a variety of animal models. Their circuit-specific spread provides a unique paradigm to study the local and global CNS response to infection. Thus, we systematically analyzed the host gene expression profile after acute pseudorabies virus (PRV) infection of the CNS using Affymetrix GeneChip technology. Rats were injected intraocularly with one of three selected virulent and attenuated PRV strains. Relative levels of cellular transcripts were quantified from hypothalamic and cerebellar tissues at various times postinfection. The number of cellular genes responding to infection correlated with the extent of virus dissemination and relative virulence of the PRV strains. A total of 245 out of 8,799 probe sets, corresponding to 182 unique cellular genes, displayed increased expression ranging from 2-to more than 100-fold higher than in uninfected tissue. Over 60% thereof were categorized as immune, proinflammatory, and other cellular defense genes. Additionally, a large fraction of infection-induced transcripts represented cellular stress responses, including glucocorticoid-and redox-related pathways. This is the first comprehensive in vivo analysis of the global transcriptional response of the mammalian CNS to acute alphaherpesvirus infection. The differentially regulated genes reported here are likely to include potential diagnostic and therapeutic targets for viral encephalitides and other neurodegenerative or neuroinflammatory diseases.

Suppression subtraction hybridization (SSH) and macroarray techniques reveal differential gene expression profiles in brain of sea bream infected with nodavirus

“…The brain was selected because is the main target of this virus. Studies on brain transcriptome against viral infections are not abundant in higher vertebrates (Gruslin et al, 2005;Paulus et al, 2006) Table 1. For the reverse library (genes up-regulated in normal tissues), there was mostly abundance of ribosomal and metabolic transcripts, revealing genes highly expressed for energy production and translation (Venier et al, 2003) (Table 2).…”

A Common Neuronal Response to Alphaherpesvirus Infection

“…Two studies did not provide any data on decreases in gene expression (Paulus et al 2006; Clement et al 2009). The trend in all studies was the observation of more increases than decreases in gene expression.…”

Suppression of the Interferon-Mediated Innate Immune Response by Pseudorabies Virus

“…Data points were considered confirmed if both methods of measurement indicated that the transcript level of the gene in question increased relative to its level in the mock sample. As has been noted previously (28), RT-PCR data tended to show even larger increases for genes whose transcript levels were highly increased by microarray analysis.…”

“…HSV-1 infection increases the mRNA and protein levels of suppressor of cytokine signaling-3 (SOCS3), a cellular inhibitor of the JAK/ STAT pathway (40). While PRV Be infection has not been shown by microarray analysis to increase SOCS3 transcript levels (28,33), it would be interesting to determine whether SOCS3 protein levels are increased after PRV infection. Other host negative regulators of STAT1 signaling that should be examined for activation by PRV infection include nuclear phosphatase TC45, cytoplasmic phosphatase PTP1B and SH2-containing phosphatases SHP1 and SHP2, PIAS proteins, and other SOCS proteins (1).…”

“…5B). PRV Ba was tested, because rats infected with this strain showed increased expression of IFN-stimulated and proinflammatory gene transcripts in their brains just before death (28). Cells infected with PRV Ba and treated with IFN contained phosphorylated STAT1, but at much lower levels than mock-infected cells (Fig.…”