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.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Line S
authors.initials: LS
authors.lastname: Reinert
authors.forename: Louis
authors.initials: L
authors.lastname: Harder
authors.forename: Christian K
authors.initials: CK
authors.lastname: Holm
authors.forename: Marie B
authors.initials: MB
authors.lastname: Iversen
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Horan
authors.forename: Frederik
authors.initials: F
authors.lastname: Dagnæs-Hansen
authors.forename: Benedicte P
authors.initials: BP
authors.lastname: Ulhøi
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Holm
authors.forename: Trine H
authors.initials: TH
authors.lastname: Mogensen
authors.forename: Trevor
authors.initials: T
authors.lastname: Owens
authors.forename: Jens R
authors.initials: JR
authors.lastname: Nyengaard
authors.forename: Allan R
authors.initials: AR
authors.lastname: Thomsen
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000821:virology*; D002531:Cerebellum / Q000821:virology; D004198:Disease Susceptibility; D005260:Female; D006561:Herpes Simplex / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000276:immunology / Q000502:physiology*; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D016899:Interferon-beta / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009187:Myelitis / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D009474:Neurons / Q000821:virology; D009928:Organ Specificity; D010264:Paraplegia / Q000209:etiology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D013116:Spinal Cord / Q000821:virology; D051196:Toll-Like Receptor 3 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016055:Urinary Retention / Q000209:etiology; D014621:Vagina / Q000276:immunology / Q000294:innervation / Q000821:virology; D056189:Viral Tropism / Q000502:physiology*; D014775:Virus Activation; D017735:Virus Latency; D000096743:Interferon gamma Receptor
chemical_list: D016899:Interferon-beta; D017471:Receptors, Interferon; D051196:Toll-Like Receptor 3; D000096743:Interferon gamma Receptor; C519703:TLR3 protein, mouse