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Effects of CXCR3 Signaling on Development of Fatal Encephalitis and Corneal and Periocular Skin Disease in HSV-Infected Mice Are Mouse-Strain Dependent

¹From the Division of Virology and the ²Departments of Immunology and ³Neurology, Beckman Research Institute, City of Hope, Duarte, California.

PURPOSE. The host inflammatory response to ocular infection with herpes simplex virus (HSV) can be either protective, with disease-free survival, or it can promote diseases such as HSV corneal disease (or herpes stromal keratitis [HSK] in humans) and encephalitis (HSE), depending on mouse strain. The role of CXCR3 chemokine signaling in HSV-induced central nervous system (CNS) inflammation and corneal disease was evaluated, and responses in genetically susceptible and resistant strains of mice were contrasted.

METHODS. Resistant C57BL/6J (B6) and susceptible 129S6 (129) mice were given monoclonal antibodies (mAbs) to neutralize the CXCR3 ligands monokine induced by interferon- (MIG, CXCL9) and interferon inducible protein-10 (IP-10, CXCL10) during HSV infection. In addition, the development of HSV disease was monitored in CXCR3-null mutant mice derived from resistant (B6) and susceptible (BALB/c) strains. Inflammatory cells infiltrating the cornea and brain stem were isolated and stained for flow cytometric analysis.

RESULTS. MIG and IP-10 were induced in nervous system tissue after HSV inoculation by the corneal route. HSV-infected 129 mice treated with MIG- or IP-10-neutralizing mAbs showed significantly enhanced survival compared with mice treated with control isotype antibody, whereas survival of the B6 mice was unaltered. Similarly, greater survival was observed for BALB.CXCR3^–/– mice compared with control BALB/c mice. Reduced CNS inflammation was documented that extended to the cornea, such that HSV corneal disease severity was reduced in susceptible BALB.CXCR3^–/–. In contrast, although survival of B6 and B6.CXCR3^–/– mice was indistinguishable, B6.CXCR3^–/– mice developed more severe corneal and periocular skin disease.

CONCLUSIONS. The effects of CXCR3 signaling in HSV infection are strongly dependent on mouse strain.

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				P. Lundberg, C. Ramakrishna, J. Brown, J. M. Tyszka, M. Hamamura, D. R. Hinton, S. Kovats, O. Nalcioglu, K. Weinberg, H. Openshaw, et al. The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice Is a Major Cause of Central Nervous System Pathology Resulting in Fatal Encephalitis J. Virol., July 15, 2008; 82(14): 7078 - 7088. [Abstract] [Full Text] [PDF]