Modulation of microglia and CD8(+) T cell activation during the development of stress-induced herpes simplex virus type-1 encephalitis.
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 (CD45(hi)) 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 CD45(hi) 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.
Nair
Aji
A
Graduate Program in Neuroscience, The Pennsylvania State University College of Medicine, Milton S Hershey Medical Center, Hershey, PA 17033, USA.
Hunzeker
John
J
Bonneau
Robert H
RH
D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D020803:Encephalitis, Herpes Simplex / Q000276:immunology* / Q000523:psychology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D013315:Stress, Psychological / Q000150:complications / Q000276:immunology* / Q000821:virology
D016207:Cytokines; D011965:Receptors, Glucocorticoid; D016194:Receptors, N-Methyl-D-Aspartate