Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis
Naoto Koyanagi, … , Akihisa Kato, Yasushi Kawaguchi
Naoto Koyanagi, … , Akihisa Kato, Yasushi Kawaguchi
Published September 11, 2017
Citation Information: J Clin Invest. 2017;127(10):3784-3795. https://doi.org/10.1172/JCI92931.
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Research Article Virology

Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis

Abstract

Herpes simplex virus–1 (HSV-1) is the most common cause of sporadic viral encephalitis, which can be lethal or result in severe neurological defects even with antiviral therapy. While HSV-1 causes encephalitis in spite of HSV-1–specific humoral and cellular immunity, the mechanism by which HSV-1 evades the immune system in the central nervous system (CNS) remains unknown. Here we describe a strategy by which HSV-1 avoids immune targeting in the CNS. The HSV-1 UL13 kinase promotes evasion of HSV-1–specific CD8+ T cell accumulation in infection sites by downregulating expression of the CD8+ T cell attractant chemokine CXCL9 in the CNS of infected mice, leading to increased HSV-1 mortality due to encephalitis. Direct injection of CXCL9 into the CNS infection site enhanced HSV-1–specific CD8+ T cell accumulation, leading to marked improvements in the survival of infected mice. This previously uncharacterized strategy for HSV-1 evasion of CD8+ T cell accumulation in the CNS has important implications for understanding the pathogenesis and clinical treatment of HSV-1 encephalitis.

Authors

Naoto Koyanagi, Takahiko Imai, Keiko Shindo, Ayuko Sato, Wataru Fujii, Takeshi Ichinohe, Naoki Takemura, Shigeru Kakuta, Satoshi Uematsu, Hiroshi Kiyono, Yuhei Maruzuru, Jun Arii, Akihisa Kato, Yasushi Kawaguchi

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Figure 7

Effect on viral pathogenicity of direct injection of CXCL9 into the brain stems of mice depleted of CD8+ T cells and ocularly infected with UL13R.

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Effect on viral pathogenicity of direct injection of CXCL9 into the brai...
Five-week-old female ICR mice depleted of CD8+ T cells were infected with 1 × 106 PFU UL13R per eye. At 5 days after infection, CXCL9 or PBS was injected into the brain stems of the infected mice. (A) At 5 and 7 days after infection, viral titers in the brains of infected mice were assayed. The results from 2 independent experiments (each with 4 mice) were combined. Each data point is the virus titer in the brain of one mouse. (B) Survival was monitored daily for 21 days. The results from 4 independent experiments (2 with 6 mice and 2 with 3 mice) were combined. The statistical significance values were analyzed by the Mann-Whitney U test (A) or the log-rank test (B).