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Chapter 9: Immunology of TBEV infection

infection there is both a systemic high level of CCR5 (receptor for CCL5), further
inflammatory response in the peripheral indicating that CCL5 acts as a chemoattractant
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tissues, as well as a localised inflammation in to recruit cells into the CNS of TBE patients.
the central nervous system (Figure 3). The neutrophil chemoattractant CXCL1 and
Numerous studies investigated the levels of CXCL2 has also been shown to be increased in
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cytokines and chemokines in serum and CSF of CSF early during TBE.
TBE patients, yet there are limited data on the
role of inflammation in the pathogenesis of In addition to chemokines, the levels of other
TBE. cytokines in the CSF of TBE patients were
assessed and correlated with clinical TBE
Early during the second phase of TBE, outcome. A significantly increased concentra-
significantly increased levels of cytokines, such tion of IFN-γ, IL-4, IL-6 and IL-8 was found in
as IL-1α, IL-2, IL-6, IL-8, IL-12, IL-15, IFN-α, IFN
the CSF of children who developed sequelae
-γ and TNF can be detected in patient serum after TBE, as compared to the children who
samples. 46,74,75 The levels of these cytokines 85
did not. In adults, low levels of IL-10 in the
decline over time. Increased levels of growth CSF later during the second phase of TBE (day
factors, such as hepatocyte growth factor and 7-18) correlated with a more severe disease.
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vascular endothelial growth factor, as well as

increased serum levels of matrix metal-
lopeptidase-9 (MMP-9) have also been found CNS immune responses during
in the sera during second phase of TBE. 75,76
Increased levels of MMP-9 highlight the TBE
presence of local inflammation within the CNS The mechanisms underlying TBE pathogenesis
in TBE patients, as increase of MMP-9 is in the CNS in humans are still largely unknown
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associated with brain tissue damage. A and under-explored. Relatively low mortality
polymorphism in MMP-9 gene (rs17576 SNP), of TBE patients and inaccessibility of brain
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which affects the function of this protein, tissue samples are the main challenges in
was also found to predispose TBE patients describing the immune mechanisms taking
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with this SNP to develop CNS damage. place in the CNS in humans. Therefore, most
Chemokines are a type of cytokines that of the research on immune cell subsets within
mediate immune cell recruitment and the CNS is performed on CSF, a fluid that is
activation in inflamed tissues. Chemokine separated from peripheral circulation via the
gradient also determines the direction for the BBB and is in direct contact with the brain and
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immune cell movement in and out of tissues. spinal cord. Even though cellular constitution
In the context of TBE patients, increased of CSF reflects which cell types selectively
CXCL9 and CXCL10 levels in the CSF were migrate through the BBB from peripheral
shown to create a chemokine gradient blood during CNS infections, it does not
between the CSF and serum, potentially necessarily fully represent the composition of
resulting in the recruitment of CXCR3 receptor the immune cells within infected brain tissue.
expressing T cells into the CNS. 80-82 Even if a However, selective migration of certain cell
gradient between the CSF and serum could types may contribute to defining the
not be confirmed for CCL5 (RANTES), CXCL11, mechanisms for pathogen clearance and
CXCL12, CXCL13, and CCL3, the concentration immunopathogenesis and may also predict
of these chemokines is also increased in the TBE disease outcome.
CSF of TBE patients. 81,83,84 The level of CCL5 in
Pathogenesis in the CNS during TBEV infection
CSF is correlated with pleocytosis, and may be attributed to direct viral effect and
activated CD4 T cells in CSF also expressed a immune-mediated tissue damage, both of

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