The central nervous system (CNS) has been shown to be vulnerable to a variety of insults in animals exposed to glucocorticoids. For example, psychological stress, a known inducer of glucocorticoid production, enhances the susceptibility of mice to herpes simplex virus type-1 (HSV-1) infection and results in the development of HSV-1 encephalitis (HSE). To determine the immune mechanisms by which stress promotes the development of HSE, we examined the role of the glucocorticoid receptor (GR) and the N-methyl-d-aspartate (NMDA) receptor in the development of HSE. Our findings demonstrate that blockade of either the GR or the NMDA receptor enhances survival following HSV-1 infection in stressed mice to levels similar to non-stressed mice. Subsequent studies determined the effect of GR and NMDA receptor blockade on immune function by specifically examining both microglia and CD8+ T cell activation. Stress inhibited the expression of MHC class I by microglia and other brain-derived antigen presenting cells (CD45hi) independent of either the glucocorticoid receptor or the NMDA receptor, suggesting that stress-induced suppression of MHC class I expression in the brain does not affect survival during HSE. Blockade of the NMDA receptor, however, diminished HSV-1-induced increases in class I expression by CD45hi cells, suggesting that blockade of the NMDA receptor may limit CNS inflammation. Also, while CD8+ T cell activation and function in the brain were not affected by stress, the number of CD8+ T cells in the superficial cervical lymph nodes (SCLN) was decreased in stressed mice via GR-mediated mechanisms. These findings indicate that stress-induced hypocellularity is mediated by the GR while NMDA receptor activation is responsible for enhancing CNS inflammation. The combined effects of GR-mediated hypocellularity of the SCLN and NMDA receptor-mediated CNS inflammation during stress promote the development of HSE.
Bibliographical noteFunding Information:
The authors thank Dr. M.E. Truckenmiller, Kathleen Ceonzo, Brandy Dacheaux, Mike Elftman, and Hassan Zawha for their helpful discussions and technical assistance. We also thank Melanie Epler for technical assistance in preparing the gB 498–505 /class I H-2K b tetramer. This work was supported by PHS Grants R01 AI49719 (RHB) and F31 MH072096 (AN).
- CD8 T cells
- Central nervous system
- Glucocorticoid receptor
- Herpes simplex virus
- NMDA receptor