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perturbations. Several families of these sensors, including certain TLRs, nucle-
otide-binding and oligomerization domain (NOD)-like receptors (NLRs),
retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and absent in
melanoma 2 (AIM2)-like receptors, have been identified
[1,9,13,14]
. The met-
abolic sensors include the mammalian target of rapamycin (mTOR), histone
deacetylase (HDAC) enzymes-sirtuins, and the inflammasomes
[13,15,16]
(see
Figure 18.1
).
Intracellular TLRs
There are 10 human TLRs and 12 mouse TLRs
[14,17,18]
. TLRs are the princi-
pal receptors of infectious agents on myeloid leukocytes, but are also found
on lymphoid leukocytes and nonhematopoietic cells. They are responsible
for sensing or recognizing various microbial agents such as viruses, bacte-
ria, fungi, and parasites
[14]
. Among these, TLRs 3, 7, 8, and 9 are present
intracellularly
[14,17,18]
. Extensive studies in inbred mice in various experi-
mental settings and in experiments of nature in humans (mutations) have
attributed key roles in immunity to these TLRs
[14,17,18]
.
TLR3
427
TLR3 preferentially recognizes dsRNA derived from the viral genome pre-
sented extracellularly, i.e., the viral genome released from damaged host
cells and/or viral particles
[18,19]
. The dsRNA molecules must be at least
40-50 bp in length to induce TLR3 signaling
[14,19]
. Analysis of the crys-
tal structure of a complex comprising TLR3 and dsRNA revealed that TLR3
binds to dsRNA molecules at two sites located at opposite ends of the
TLR3 horseshoe
[20,21]
. Furthermore, data also suggest that TLR3 primar-
ily senses unmethylated RNA molecules
[22]
. TLR3 is mainly expressed in
hematopoietic cells, particularly in subsets of dendritic cells (DCs), but also
in some stromal cells. TLR3 detects dsRNA, which gains access to the endo-
somal compartment by phagocytosis of virus-infected cells or apoptotic cell
debris, internalization of antibodies bound to viruses, or autophagy
[23,24]
.
Spatial localization is important for recognition of viral dsRNA by TLR3, as
cell-associated dsRNA has been found to be a more potent activator of TLR3
than soluble dsRNA
[14,18]
. Nucleic acid sensing by TLR3 mediates the type
I interferon (IFN) response. TLR3 transmits signals through the TRIF path-
way, which induces phosphorylation and nuclear translocation of IRF3,
resulting in the transcription and secretion of IFN-β
[14,25]
. TLR3-TRIF
signaling also activates nuclear factor κB (NF-κB) and the transcription
of inflammatory cytokine genes
[14,19]
. The specificity of TLR3 for dsRNA
allows recognition of RNA viruses, namely, influenza A, West Nile, and rhi-
novirus, among others
[26]
. Data also suggest that TLR3 can detect certain
DNA viruses such as herpes simplex virus 1 (HSV-1)
[27-29]
. The ability to
detect DNA viruses is surprising, although this may still be through the rec-
ognition of RNA intermediates that are likely to have been generated during
viral replication. The infectious phenotypes of TLR3-deficient mice dem-
onstrate a broad vulnerability to experimental viral infections, although,
surprisingly, they are also more resistant than controls to some other infec-
tions
[26]
. The reasons for the increased resistance remain unknown. The
induction of the type I IFN immune responses by the recognition of dsRNA
by TLR3 can enhance adaptive immune responses
[1]
. Poly(I:C), a synthetic
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