TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice
Line S. Reinert, … , Allan R. Thomsen, Søren R. Paludan
Line S. Reinert, … , Allan R. Thomsen, Søren R. Paludan
Published March 19, 2012
Citation Information: J Clin Invest. 2012;122(4):1368-1376. https://doi.org/10.1172/JCI60893.
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TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice

Abstract

Herpes simplex viruses (HSVs) are highly prevalent neurotropic viruses. While they can replicate lytically in cells of the epithelial lineage, causing lesions on mucocutaneous surfaces, HSVs also establish latent infections in neurons, which act as reservoirs of virus for subsequent reactivation events. Immunological control of HSV involves activation of innate immune pattern-recognition receptors such as TLR3, which detects double-stranded RNA and induces type I IFN expression. Humans with defects in the TLR3/IFN pathway have an elevated susceptibility to HSV infections of the CNS. However, it is not known what cell type mediates the role of TLR3 in the immunological control of HSV, and it is not known whether TLR3 sensing occurs prior to or after CNS entry. Here, we show that in mice TLR3 provides early control of HSV-2 infection immediately after entry into the CNS by mediating type I IFN responses in astrocytes. Tlr3–/– mice were hypersusceptible to HSV-2 infection in the CNS after vaginal inoculation. HSV-2 exhibited broader neurotropism in Tlr3–/– mice than it did in WT mice, with astrocytes being most abundantly infected. Tlr3–/– mice did not exhibit a global defect in innate immune responses to HSV, but astrocytes were defective in HSV-induced type I IFN production. Thus, TLR3 acts in astrocytes to sense HSV-2 infection immediately after entry into the CNS, possibly preventing HSV from spreading beyond the neurons mediating entry into the CNS.

Authors

Line S. Reinert, Louis Harder, Christian K. Holm, Marie B. Iversen, Kristy A. Horan, Frederik Dagnæs-Hansen, Benedicte P. Ulhøi, Thomas H. Holm, Trine H. Mogensen, Trevor Owens, Jens R. Nyengaard, Allan R. Thomsen, Søren R. Paludan

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Figure 1

Tlr3–/– mice are hypersusceptible to HSV-2 infection.

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Tlr3–/– mice are hypersusceptible to HSV-2 infection. Disease devel...
Disease development after intravaginal infection with HSV-2 (6.7 × 104 PFU). (A) Clinical score of infected mice from day 1–6 p.i. (B) Percentage of animals with hind limb paralysis on day 6 p.i. (C) Percentage of animals with bladder retention on day 6 p.i. (D) Post-mortem urinary retention (white arrow), constipation (blue arrow), and fatty liver (yellow arrow) were observed in the infected Tlr3–/– mice. (E) H&E-stained medulla spinalis (original magnification, ×200), cerebellum and cerebrum sections (original magnification, ×40) of infected mice day 6 p.i. Second column: staining of medulla spinalis sections with anti-CD45. CD45+ cells are indicated by black arrow (original magnification: ×400). The data shown in (A–C) are mean of 3–5 independent experiments on day 6 p.i. (n = 4–12 mice in each group per experiment), and (D) are representative pictures of these experiments. *P < 0.05.