Prolonged microglial cell activation and lymphocyte infiltration following experimental herpes encephalitis

CP Marques, MCJ Cheeran, JM Palmquist… - The Journal of …, 2008 - journals.aai.org
CP Marques, MCJ Cheeran, JM Palmquist, S Hu, SL Urban, JR Lokensgard
The Journal of Immunology, 2008journals.aai.org
Experimental murine herpes simplex virus (HSV)-1 brain infection stimulates microglial cell-
driven proinflammatory chemokine production which precedes the presence of brain-
infiltrating systemic immune cells. In the present study, we investigated the phenotypes and
infiltration kinetics of leukocyte trafficking into HSV-infected murine brains. Using real-time
bioluminescence imaging, the infiltration of luciferase-positive splenocytes, transferred via
tail vein injection into the brains of HSV-infected animals, was followed over an 18-day time …
Abstract
Experimental murine herpes simplex virus (HSV)-1 brain infection stimulates microglial cell-driven proinflammatory chemokine production which precedes the presence of brain-infiltrating systemic immune cells. In the present study, we investigated the phenotypes and infiltration kinetics of leukocyte trafficking into HSV-infected murine brains. Using real-time bioluminescence imaging, the infiltration of luciferase-positive splenocytes, transferred via tail vein injection into the brains of HSV-infected animals, was followed over an 18-day time course. Flow cytometric analysis of brain-infiltrating leukocytes at 5, 8, 14, and 30 days postinfection (dpi), was performed to assess their phenotype. A predominantly macrophage (CD45 high CD11b+ Ly6C high) and neutrophil (CD45 high CD11b+ Ly6G+) infiltration was seen early during infection, with elevated levels of TNF-α mRNA expression. By 14 dpi, the phenotypic profile shifted to a predominantly lymphocytic (CD45 high CD3+) infiltrate. This lymphocyte infiltrate was detected until 30 dpi, when infectious virus could not be recovered, with CD8+ and CD4+ T cells present at a 3: 1 ratio, respectively. This T lymphocyte infiltration paralleled increased IFN-γ mRNA expression in the brain. Activation of resident microglia (CD45 int CD11b+) was also detected until 30 dpi, as assessed by MHC class II expression. Activated microglial cells were further identified as the predominant source of IL-1β. In addition, infected mice given primed immunocytes at 4 dpi showed a significant increase in mortality. Taken together, these results demonstrate that intranasal infection results in early macrophage and neutrophil infiltration into the brain followed by prolonged microglial activation and T lymphocyte retention. Similar prolonged neuroimmune activation may contribute to the neuropathological sequelae observed in herpes encephalitis patients.
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