toll-like receptors in cns viral infections
DESCRIPTION
Toll-Like Receptors in CNS Viral Infections. Unclear role of TLRs in natural infections TLR3, -7, -8, -9 recognize viral nucleic acids. Localized intracellularly in endosomal compartments Ligands for TLR3: - dsRNA (Reovirus) - dsRNA intermediates (RNA, DNA viruses) - PowerPoint PPT PresentationTRANSCRIPT
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Toll-Like Receptors in CNS Viral InfectionsToll-Like Receptors in CNS Viral Infections
• Unclear role of TLRs in natural infections
• TLR3, -7, -8, -9 recognize viral nucleic acids.Localized intracellularly in endosomal compartments
• Ligands for TLR3: - dsRNA (Reovirus)- dsRNA intermediates (RNA, DNA viruses)- cellular RNA, released upon tissue damage (ssRNA, mRNA)
• TLR3 is expressed abundantly in astrocytes, as well as in microglial cells and neurons upon viral infections and brain disorders
Menager et al. PLoS Pathog 5(2): e1000315. doi:10.1371/journal.ppat.1000315; Tammy Kielian. Toll-like Receptors: Roles in Infection and Neuropathology. Current Topics in Microbiology and Immunology ISSN 0070-217x
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Herpes Simplex Life CycleHerpes Simplex Life Cycle
Frampton et al. Gene Therapy (2005) 12,
891–901. doi:10.1038/sj.gt.3302545
a) Primary lytic infection of epithelial or mucosal cells;
b) Progeny viral particles are transported to nerve cell body. Virus can be spread to CNS, or
c) Viral genome can persist as a latent episome within the neuron;
d) Upon stimulation virus can reactivate and travel to neuron termini;
e) Virus initiates productive recurrent infection upon encountering an epithelial or mucosal cell.
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Herpes Simplex Encephalitis (HSE)Herpes Simplex Encephalitis (HSE)
• severe viral infection of the human central nervous system
• affects at least 1 in 500,000 individuals per year
• both primary and recurrent HSV infections can cause disease of the CNS
• the route of access of virus to the CNS in primary infection, especially in humans, is a subject of debate. Classic studies defined pathways for access of HSV to the brain in animals and include both the olfactory and trigeminal nerves among others
• IRAK4-deficient patients (fail to signal through TLR7, -8 and -9) are not succeptible to HSE
• UNC93B-deficient patients (fail to signal through TLR3, -7, 8- and -9) display impaired TLR3-dependent IFN-, -, - production
http://pathology.mc.duke.edu/neuropath/CNSlecture2/hsv.jpg
Whitley. Herpes simplex encephalitis: Adolescents and adults. Antiviral Res. 2006 Sep;71(2-3):141-8.
Impaired TLR3-dependent induction of IFN-, -, - is involved in HSE
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A Heterozygous TLR3 Mutation in Two A Heterozygous TLR3 Mutation in Two Children with HSEChildren with HSE
The P554S TLR3 mutation conferred an autosomal dominant predisposition to HSE with incomplete clinical penetrance.
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Impaired Responsiveness of Fibroblasts to Impaired Responsiveness of Fibroblasts to Poly(I:C) StimulationPoly(I:C) Stimulation
The cosegregation of genotype and fibroblastic phenotype suggests that heterozygosity for the P554S TLR3 allele confers autosomal dominant hyporesponsiveness to poly(I:C) in fibroblasts.
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Dominant-negative Effect of the P554S Dominant-negative Effect of the P554S TLR3TLR3 Allele in Fibroblasts Allele in Fibroblasts
The P554S TLR3 protein is C-terminally truncated. P554S mutation leads to loss-of-function for poly(I:C) responsiveness, and is dominant negative in fibroblasts, at least for IFN induction.
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Impaired IFN-dependent Control of Viruses Impaired IFN-dependent Control of Viruses in TLR3-deficient Fibroblastsin TLR3-deficient Fibroblasts
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The P554S TLR3 mutation leads to TLR3 impaired signaling, abnormally weak IFN-/ and – production, enhanced viral replication, and higher levels of fibroblast cell death upon viral infection.
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Impaired Response to Poly(I:C) Stimulation Impaired Response to Poly(I:C) Stimulation in MDDCs, NK and CD8 T Cellsin MDDCs, NK and CD8 T Cells
TLR3 mutation affects heterozygous children, but contribution of NK cells and CD8 T cells to the pathogenesis of HSE is probably modest.
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Response of Blood DCs and Keratinocytes Response of Blood DCs and Keratinocytes to Poly(I:C) Stimulationto Poly(I:C) Stimulation
The lack of clinical HSV-1 dissemination by the blood in patients with HSE may be due to the induction of IFNs by MDCs and PDCs stimulated with dsRNA and other viral intermediates.
HSV-1 does not spread to epithelia during or following HSE.
The poly(I:C) responsiveness of DCs and keratinocytes probably operated through TLR3-independent pathways, although residual TLR3 signaling or lack of dominance of P554S TLR3 mutant cannot be excluded in these cells.
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Most Viruses Trigger IFNs in TLR3 Most Viruses Trigger IFNs in TLR3 Heterozygous CellsHeterozygous Cells
Induction of IFN-, - and –in blood cells and fibroblasts from TLR3-heterozygous patients after stimulation with most of the viruses tested, was consistent with the natural resistance of these patients to most viruses other than HSV-1.
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ConclusionsConclusions• After autosomal recessive UNC93B-deficiency, autosomal dominant TLR3
deficiency was identified as the second genetic etiology of isolated HSE.• Molecular pathogenesis of HSE primarily involves impaired TLR3-dependent IFN-, - and - responses. Pathogenic cellular mechanism involves intrinsic defect affecting CNS-resident cells:
- neurotropic infection of the CNS by HSV-1,
- CNS-restricted clinical course of HSE,
- preferential expression of TLR3 in CNS,
- poly(I:C) inducible production of antiviral IFNs by blood DCs in TLR3 heterozygotes,
- the absence of HSE in patients with conventional primary immunodeficiencies.
• The findings provide further support for the treatment of HSE patients with IFN- in addition to acyclovir.
• TLR3-deficiency appears to be redundant in antiviral immunity, in humans as well as in mice. Nevertheless, human TLR3 is essential for primary immunity to HSV-1 in the CNS (although multiple factors may affect clinical penetrance: age at infection with HSV-1, viral inoculum, and human modifier genes).