Viral Induction of Central Nervous System Innate Immune Responses

Abstract

The ability of the central nervous system (CNS) to generate innate immune responses was investigated in an in vitro model of CNS infection. Cultures containing CNS cells were infected with mouse hepatitis virus-JHM, which causes fatal encephalitis in mice. Immunostaining indicated that viral infection had a limited effect on culture characteristics, overall cell survival, or cell morphology at the early postinfection times studied. Results from Affymetrix gene array analysis, assessed on RNA isolated from virally and sham-infected cultures, were compared with parallel protein assays for cytokine, chemokine, and cell surface markers. Of the 126 transcripts found to be differentially expressed between viral and sham infections, the majority were related to immunological responses. Virally induced increases in interleukin-6 and tumor necrosis factor alpha mRNA and protein expression correlated with the genomic induction of acute-phase proteins. Genomic and protein analysis indicated that viral infection resulted in prominent expression of neutrophil and macrophage chemotactic proteins. In addition, mRNA expression of nonclassical class I molecules H2-T10, -T17, -M2, and -Q10, were enhanced three-to fivefold in virus-infected cells compared to sham-infected cells. Thus, upon infection, resident brain cells induced a breadth of innate immune responses that could be vital in directing the outcome of the infection and, in vivo, would provide signals which would summon the peripheral immune system to respond to the infection. Further understanding of how these innate responses participate in immune protection or immunopathology in the CNS will be critical in efforts to intervene in severe encephalitis.

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

“…However, given the complexity of the infected tissue, it is virtually impossible to determine what responses reflect directly infected cells and indirect responses of uninfected tissue. The list of rat CNS genes that respond to PRV infection is remarkably similar to those genes responsive to rodent CNS infection by diverse agents such as mouse hepatitis virus (52), prions (75), and West Nile virus (68). It is likely that the rodent CNS response to infection is not tailored to a specific infectious agent but rather represents a conserved defensive reaction to neuronal damage characterized by a vigor-ous intrinsic and innate immune response, followed by the infiltration of adaptive immune cells from the periphery.…”

Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

“…In addition, post-mortem sections from the temporal lobes of patients who suffered seizures as a result of HSV infection show robust pro-inflammatory infiltrates relative to other brain regions (Chadwick, 2005;Esiri, 1982;Jay et al, 1998;Theodore et al, 2008;Yamada et al, 2003). These findings have led some to suspect that the epileptogenicity of viral encephalitis results from the recruitment of the hippocampus causing long-term excitability (Chen et al, 2004;Wu et al, 2003), even in the absence of acute or chronic cytological injury (Beers et al, 1993;Rempel et al, 2005); while others have proposed that marked neuronal damage contributes to the hyperexcitable state (Pearce et al, 1996).…”

The Cellular Antiviral Protein Viperin Is Attenuated by Proteasome-Mediated Protein Degradation in Japanese Encephalitis Virus-Infected Cells

“…Viperin was then found to be induced by both type I and type II IFN and to exhibit antiviral activity against HCMV (9). Furthermore, the results of several gene-profiling microarray studies showed that the viperin gene is one of those that is highly induced by a range of different viruses (20,25,38,40,42,46) and microbial products, such as lipopolysaccharide (35,42), the double-stranded RNA analog poly(I-C) (39), and double-stranded B-form DNA (22), in various cell types.The human viperin gene encodes a protein of 361 amino acids with a predicted molecular mass of 42.2 kDa. Protein sequence analysis reveals a CX 3 CX 2 C motif, which is found in the superfamily of S-adenosyl methionine (SAM)-dependent radical enzymes (44) in residues 83 to 90 of human viperin.…”