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 1

Effect of HSV-1 UL13 kinase activity on viral replication and pathogenicity in the CNS of mice following ocular infection.

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Effect of HSV-1 UL13 kinase activity on viral replication and pathogenic...
(A) Five-week-old female ICR mice were ocularly infected with 1 × 106 PFU UL13KM or UL13R per eye and monitored for survival daily for 14 days. The results of 3 independent experiments (1 with 5 mice and 2 with 10 mice) were combined. (B) At 5 and 8 days after infection, the brains of infected mice were harvested, sectioned, stained with an antibody to HSV-1 antigens, and analyzed by fluorescence microscopy. In each row, the first and third images are of different sections, and the second and fourth images are higher magnifications of the boxed areas of the sections in the first and third images, respectively. Magnification of first and third images, 4× objective lens. Scale bars: 2 mm. Magnification of second and fourth images, 20× objective lens. Scale bars: 200 μm. d.p.i., day(s) after infection. (C) Viral titers in the brains of infected mice at 1, 3, 5, 7, and 8 days after infection were assayed. Dashed line indicates the limit of detection. The results of 3 independent experiments (1 with 7 mice and 2 with 5 mice) were combined for each virus. Each data point is the virus titer in the brain of one mouse. Statistical significance values were analyzed by the log-rank test (A) or the Mann-Whitney U test (C).