TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice

Line Reinert; Louis Andreas Harder; Christian Holm; Marie Beck Iversen; Kristy Amanda Horan; Frederik Dagnæs-Hansen; Benedicte Parm Ulhøi; Thomas Holm; Trine Mogensen; Trevor Owens; Jens Randel Nyengaard; Allan Randrup Thomsen; Søren R Paludan

doi:10.1172/JCI60893

TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice

Line Reinert, Louis Andreas Harder, Christian Holm, Marie Beck Iversen, Kristy Amanda Horan, Frederik Dagnæs-Hansen, Benedicte Parm Ulhøi, Thomas Holm, Trine Mogensen, Trevor Owens, Jens Randel Nyengaard, Allan Randrup Thomsen, Søren R Paludan

Department of Immunology and Microbiology

116 Citations (Scopus)

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.

Original language	English
Journal	Journal of Clinical Investigation
Volume	122
Issue number	4
Pages (from-to)	1368-1376
Number of pages	9
ISSN	0021-9738
DOIs	https://doi.org/10.1172/JCI60893
Publication status	Published - 2 Apr 2012

Keywords

Animals
Astrocytes
Cerebellum
Disease Susceptibility
Female
Herpes Simplex
Herpesvirus 2, Human
Immunity, Innate
Immunity, Mucosal
Interferon-beta
Mice
Mice, Inbred C57BL
Mice, Knockout
Myelitis
Neurons
Organ Specificity
Paraplegia
Receptors, Interferon
Spinal Cord
Toll-Like Receptor 3
Urinary Retention
Vagina
Viral Tropism
Virus Activation
Virus Latency

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/JCI60893

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Reinert, L., Harder, L. A., Holm, C., Iversen, M. B., Horan, K. A., Dagnæs-Hansen, F., Ulhøi, B. P., Holm, T., Mogensen, T., Owens, T., Nyengaard, J. R., Thomsen, A. R., & Paludan, S. R. (2012). TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice. Journal of Clinical Investigation, 122(4), 1368-1376. https://doi.org/10.1172/JCI60893

Reinert, L, Harder, LA, Holm, C, Iversen, MB, Horan, KA, Dagnæs-Hansen, F, Ulhøi, BP, Holm, T, Mogensen, T, Owens, T, Nyengaard, JR, Thomsen, AR & Paludan, SR 2012, 'TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice', Journal of Clinical Investigation, vol. 122, no. 4, pp. 1368-1376. https://doi.org/10.1172/JCI60893

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title = "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.",

keywords = "Animals, Astrocytes, Cerebellum, Disease Susceptibility, Female, Herpes Simplex, Herpesvirus 2, Human, Immunity, Innate, Immunity, Mucosal, Interferon-beta, Mice, Mice, Inbred C57BL, Mice, Knockout, Myelitis, Neurons, Organ Specificity, Paraplegia, Receptors, Interferon, Spinal Cord, Toll-Like Receptor 3, Urinary Retention, Vagina, Viral Tropism, Virus Activation, Virus Latency",

author = "Line Reinert and Harder, {Louis Andreas} and Christian Holm and Iversen, {Marie Beck} and Horan, {Kristy Amanda} and Frederik Dagn{\ae}s-Hansen and Ulh{\o}i, {Benedicte Parm} and Thomas Holm and Trine Mogensen and Trevor Owens and Nyengaard, {Jens Randel} and Thomsen, {Allan Randrup} and Paludan, {S{\o}ren R}",

year = "2012",

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day = "2",

doi = "10.1172/JCI60893",

language = "English",

volume = "122",

pages = "1368--1376",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

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TY - JOUR

T1 - TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice

AU - Reinert, Line

AU - Harder, Louis Andreas

AU - Holm, Christian

AU - Iversen, Marie Beck

AU - Horan, Kristy Amanda

AU - Dagnæs-Hansen, Frederik

AU - Ulhøi, Benedicte Parm

AU - Holm, Thomas

AU - Mogensen, Trine

AU - Owens, Trevor

AU - Nyengaard, Jens Randel

AU - Thomsen, Allan Randrup

AU - Paludan, Søren R

PY - 2012/4/2

Y1 - 2012/4/2

N2 - 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.

AB - 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.

KW - Animals

KW - Astrocytes

KW - Cerebellum

KW - Disease Susceptibility

KW - Female

KW - Herpes Simplex

KW - Herpesvirus 2, Human

KW - Immunity, Innate

KW - Immunity, Mucosal

KW - Interferon-beta

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Myelitis

KW - Neurons

KW - Organ Specificity

KW - Paraplegia

KW - Receptors, Interferon

KW - Spinal Cord

KW - Toll-Like Receptor 3

KW - Urinary Retention

KW - Vagina

KW - Viral Tropism

KW - Virus Activation

KW - Virus Latency

U2 - 10.1172/JCI60893

DO - 10.1172/JCI60893

M3 - Journal article

C2 - 22426207

SN - 0021-9738

VL - 122

SP - 1368

EP - 1376

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 4

ER -

TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice

Abstract

Keywords

UN SDGs

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