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 October 2, 2017; First 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 6

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

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Effect of direct injection of CXCL9 into the brain stems of mice ocularl...
(A–G) Five-week-old female ICR mice were ocularly 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. At 7 days after infection, brain stem (A and E) and submandibular lymph node (B and F) samples were processed and analyzed for CD8+ T (CD8+, CD3+, and CD45+) (A and B) or CD4+ T (CD4+, CD3+, and CD45+) (E and F) cell content by flow cytometry. At 7 days after infection, CD8+ T cells purified from brain stem (C) and submandibular lymph node samples (D) were assayed for IFN-γ–producing cell content by ELISPOT assays. At 5 and 7 days after infection, viral titers in the brains of infected mice were assayed (G). The results from 3 independent experiments (each with 4 mice) were combined. Each data point is the number of each type of cells in each tissue of one mouse (A–F) or the virus titer in the brain of one mouse (G). (H) Survival was monitored daily for 21 days. The results from 4 independent experiments (1 with 5 mice and 3 with 6 mice for the CXCL9 injection experiments; and 1 with 3 mice, 1 with 4 mice, and 2 with 5 mice for the PBS injection experiments) were combined. The statistical significance values were analyzed by the Mann-Whitney U test (A–G) or the log-rank test (H).