Transcript Impaired TLR3-dependent induction of IFN-a, -b,

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)
- 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
Herpes Simplex Life Cycle
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.
Frampton et al. Gene Therapy (2005) 12,
891–901. doi:10.1038/sj.gt.3302545
Herpes Simplex Encephalitis (HSE)
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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-a, -b, -l
production
http://pathology.mc.duke.edu/
neuropath/CNSlecture2/hsv.jpg
Impaired TLR3-dependent induction of IFN-a, -b, -l is involved in HSE
Whitley. Herpes simplex encephalitis: Adolescents and adults. Antiviral Res. 2006 Sep;71(2-3):141-8.
A Heterozygous TLR3 Mutation in Two
Children with HSE
The P554S TLR3 mutation conferred an autosomal dominant predisposition to
HSE with incomplete clinical penetrance.
Impaired Responsiveness of Fibroblasts to
Poly(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.
Dominant-negative Effect of the P554S
TLR3 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.
Impaired IFN-dependent Control of Viruses
in TLR3-deficient Fibroblasts
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The P554S TLR3 mutation leads to TLR3 impaired signaling, abnormally weak
IFN-a/b and –l production, enhanced viral replication, and higher levels of
fibroblast cell death upon viral infection.
Impaired Response to Poly(I:C) Stimulation
in 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.
Response of Blood DCs and Keratinocytes
to 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.
Most Viruses Trigger IFNs in TLR3
Heterozygous Cells
Induction of IFN-a, -b and –l
in
blood
cells
and
fibroblasts
from
TLR3heterozygous 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.
Conclusions
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After autosomal recessive UNC93B-deficiency, autosomal dominant TLR3
deficiency was identified as the second genetic etiology of isolated HSE.
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Molecular pathogenesis of HSE primarily involves impaired TLR3dependent IFN-a, -b and -l 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.
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The findings provide further support for the treatment of HSE patients with
IFN-a in addition to acyclovir.
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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).