Toll-like receptor 2 signaling is a mediator of apoptosis in herpes simplex virus-infected microglia.
BACKGROUND
Information regarding the response of brain cells to infection with herpes simplex virus (HSV)-1 is needed for a complete understanding of viral neuropathogenesis. We have recently demonstrated that microglial cells respond to HSV infection by producing a number of proinflammatory cytokines and chemokines through a mechanism involving Toll-like receptor 2 (TLR2). Following this cytokine burst, microglial cells rapidly undergo cell death by apoptosis. We hypothesized that TLR2 signaling might mediate the cell death process as well.


METHODS
To test this hypothesis, we investigated HSV-induced cell death of microglia obtained from both wild-type and TLR2-/- mice. Cell death was studied by oligonucleosomal ELISA and TUNEL staining, and the mechanisms of apoptosis were further analyzed using murine apoptosis-specific microarrays. The data obtained from microarray analysis were then validated using quantitative real-time PCR assays.


RESULTS
HSV infection induced apoptotic cell death in microglial cells from wild-type as well as TLR2 cells. However, the cell death at 24 h p.i. was markedly lower in knockout cells. Furthermore, microarray analyses clearly showed that the expression of pro-apoptotic genes was down-regulated at the time when wild-type cells were actively undergoing apoptosis, indicating a differential response to HSV in cells with or without TLR2.


CONCLUSIONS
We demonstrate here that HSV induces an apoptotic response in microglial cells which is mediated through TLR2 signaling.
Aravalli
Rajagopal N
RN
Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, MN 55455, USA. arava001@umn.edu <arava001@umn.edu>
Hu
Shuxian
S
Lokensgard
James R
JR
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D015967:Gene Expression Regulation, Viral / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018139:Simplexvirus / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2