Page 113 - TBE_Book_V2_2019

Chapter 5: TBE in adults

epithelial and endothelial cells, fibroblasts, These findings were confirmed by a large
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different populations of mononuclear cohort study from Lithuania and a trial from
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leukocytes, as well as neurons and glial Russia. In the Lithuanian cohort study, which
cells. 14,16–19 TLR3 is present in different types enrolled adult and pediatric TBE cases, the
of glial cells within the central nervous system TLR3 polymorphism, rs3775291, was found to
(CNS) and its expression is upregulated during be less prevalent in the combined adult/
CNS inflammation. However, some viruses pediatric TBE cohort than in the healthy
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seem to suppress or bypass TLR3 signaling, at control group. In the Russian analyses, which
least in some types of cells. For example, investigated 137 non-vaccinated TBE patients
herpes simplex virus type 1 (HSV1) induces for the presence of the rs3775291 poly-
only a limited response in human neurons morphism compared with a healthy control
expressing TLR3, with no type 1 IFN group (n=239), it was concluded that a
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synthesis. functioning, wildtype TLR3 seems to be a risk
factor for TBE.
Data from WNV infections suggest that there
is a link between genetic risk factors and 2’-5’ Oligoadenylate synthetase
severe clinical courses; however, findings are, (IFN-induced oligoadenylate
in part, inconsistent. WNV entry into the CNS synthetase 2 (OAS2) and IFN-induced
depends on the expression of TLR3 as an
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important cofactor. Knockout of TLR3 results oligoadenylate synthetase 3 (OAS3))
in higher peripheral viral load, reduced CNS
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viral load, and inflammation of the brain. 2’-5’ Oligoadenylate synthetase is an IFN-
induced anti-viral protein that catalyzes
The detrimental effects of TLR3 stimulation
depend on the activation of tumor necrosis oligomerization of ATP into 2’,5’- linked
factor-α (TNF-α) receptor 1, suggesting that oligoadenylate (2-5A), which in turn activates
latent RNase L. Activated RNase L is able to
TNF-α is a downstream mediator of TLR3-
induced blood–brain barrier permeability. 21 degrade viral RNA, particularly RNA from
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neurotropic viruses. The human OAS gene
However, knockout of TLR3 reduces the
inflammatory response and thus neuronal family comprises 4 genes, of which 3: OAS1,
damage in the CNS, irrespective of the local OAS2, and OAS3 encode functional OAS, which
viral load. 21 by alternative splicing may be expressed in 8
different isoforms: 5 of OAS1 (p42, p44, p46,
For TBEV, the exact mechanism of entry to the p48, and p52), 2 of OAS2 (p69 and p71), and a
CNS is not known. 22–24 It is speculated that, single OAS3 isoform (p100). OASL encodes 2
very similar to WNV, TBEV enters the CNS isoforms of the OASL protein (p30, p59) which
after an intense peripheral inflammatory lacks OAS enzymatic activity. OAS1 and OAS2
response disrupts the blood–brain barrier, or synthesize mainly 2-5A oligomers and OAS3
25 mainly (but probably not exclusively) dimers,
via olfactory neurons. Investigating the
clinical relevance of these findings from which do not activate RNase L, but may
animal studies, a clinical study analyzed the initiate alternative antiviral pathways.
frequency of 2 TLR3 mutations in 128 TBE Particular isoforms of OAS1 and OAS2 differ in
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patients from Lithuania, presumably infected their activity and intracellular distribution.
with the European subtype of TBEV (TBEV-EU). Constitutive OAS activity is individually
There were 2 control groups: 1 consisted of 77 variable and strongly correlated between
patients with aseptic meningitis and the close relatives, suggesting that genetic factors
second comprised 135 healthy individuals determine activity. In theory, single nucleotide
from the same region. Results indicated that polymorphisms (SNPs) in all the genes of the
fully-functioning TLR3 is a risk factor for TBE. OAS complex could contribute to the

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