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Intranasal herpes simplex virus type 2 inoculation causes a profound thymidine kinase dependent cerebral inflammatory response in the mouse hindbrain
Author(s) -
Boivin Guy,
Coulombe Zoé,
Rivest Serge
Publication year - 2002
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2002.02057.x
Subject(s) - herpes simplex virus , biology , chemokine , immunology , thymidine kinase , tlr2 , tumor necrosis factor alpha , virology , virus , immune system , innate immune system
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‐κB) 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 κBα (IκBα, index of NF‐κB activity), toll‐like receptor 2 (TLR2), tumour necrosis factor α (TNF‐α) 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.