Intranasal herpes simplex virus type 2 inoculation causes a profound thymidine kinase dependent cerebral inflammatory response in the mouse hindbrain.
The herpes simplex virus (HSV) has the ability to replicate in the central nervous system (CNS), which may cause fatal encephalitis. The present study investigated the activity of the nuclear factor kappa B (NF-kappa B) and the pattern of cytokine/chemokine gene expression across the brain of HSV-infected mice and the role of the viral thymidine kinase (TK) in mediating these effects. Mice were killed 1-8 days after intranasal inoculation with either HSV-2 TK-competent or TK-deficient clinical isolates. Animals infected with the TK-competent virus exhibited first signs of infection at day 5 postinoculation, whereas severe signs of sickness were observed between day 6 and 8. A robust hybridization signal was found in the brain of these animals for the gene encoding the inhibitory factor kappa B alpha (I kappa B alpha, index of NF-kappa B activity), toll-like receptor 2 (TLR2), tumour necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) in numerous regions of the pons and medulla. The levels of expression of these genes increased 4 days after the inoculation and peaked at day 6 within the endothelium of the brain capillaries and cells of myeloid origin. A robust signal for the TK gene and its encoding protein was detected selectively within the regions that exhibited expression of the immune molecules. In contrast, animals that received the TK-deficient virus did not show any signs of sickness or cerebral inflammation or HSV replication within the cerebral tissue. The present data provide clear evidence that HSV-2 has the ability to trigger a profound inflammatory response in a pattern that follows the viral TK-dependent HSV replication in neurons. Such neurovirulence occurring in the hindbrain is proposed here to be directly responsible for neurodegeneration and to lead to the cerebral innate immune response, which in turn could play a key role in fatal HSV-2-induced encephalitis.
Boivin
Guy
G
Laboratory of Infectious Diseases, CHUL Research Centre and Laval University, 2705, boul. Laurier, Québec, G1V 4G Canada.
Coulombe
Zoé
Z
Rivest
Serge
S
D000281:Administration, Intranasal; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins; D005260:Female; D018258:Herpesvirus 2, Human / Q000472:pathogenicity*; D020672:I-kappa B Proteins; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation / Q000201:enzymology / Q000821:virology; D007371:Interferon-gamma / Q000378:metabolism; D008526:Medulla Oblongata / Q000201:enzymology / Q000821:virology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011149:Pons / Q000201:enzymology / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012249:Rhombencephalon / Q000201:enzymology* / Q000821:virology*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma; D013937:Thymidine Kinase