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Prolonged Microglial Cell Activation and Lymphocyte Infiltration following Experimental Herpes Encephalitis¹

Cristina P. Marques^*, Maxim C-J. Cheeran^2,*,, Joseph M. Palmquist^*, Shuxian Hu^*, Stina L. Urban^* and James R. Lokensgard^*

^* Center for Infectious Diseases and Microbiology Translational Research, Department of Medicine, University of Minnesota Medical School, and Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, Minneapolis, MN 55455

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 (d.p.i.), was performed to assess their phenotype. A predominantly macrophage (CD45^highCD11b⁺Ly6C^high) and neutrophil (CD45^highCD11b⁺Ly6G⁺) infiltration was seen early during infection, with elevated levels of TNF- mRNA expression. By 14 d.p.i., the phenotypic profile shifted to a predominantly lymphocytic (CD45^highCD3⁺) infiltrate. This lymphocyte infiltrate was detected until 30 d.p.i., 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- mRNA expression in the brain. Activation of resident microglia (CD45^intCD11b⁺) was also detected until 30 d.p.i., 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 d.p.i. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by United States Public Health Service Grant MH-066703, the University of Minnesota Graduate School Doctoral Dissertation Fellowship, and the University of Minnesota AHC Faculty Development Grant.

² Address correspondence and reprint requests to Dr. Maxim C-J. Cheeran, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, 3–222 LRB/MTRF, 2001 Sixth Street SE, Minneapolis, MN 55455. E-mail address: cheeran{at}umn.edu

³ Abbreviations used in this paper: HSV, herpes simplex virus; d.p.i., days p.i.

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