Page 179 - TBE_Book_V2_2019

Chapter 9: Immunology of TBEV infection

which are supported by the detection of TBEV In mouse models, TBEV infection induces CCL5
viral proteins and immune cell infiltrates in expression accompanied by increased immune
3,4
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neuronal tissues from cases of fatal TBE. The cell infiltration into the CNS. Blocking of CCL5
mechanism for virus passage through the BBB reduced cell infiltration and extended the
into the brain is not yet defined, as discussed survival of mice after TBEV infection. In vitro
more in detail under the section “Viral TBEV infection of human glioblastoma cell
dissemination and entry into the CNS”. lines and primary astrocytes by TBEV
Neurons are believed to be the primary demonstrated that increased CCL5 expression
targets for TBEV in the CNS, 3,87 but other brain is mediated by the viral TBEV protein NS5. 94,95
cells are also infected in vitro. 15-17
An integrin role in T cell CNS recruitment
Immune cell infiltration into the CSF, defined during TBE is discussed in a recent study on
as pleocytosis, is a common event during CNS TBEV-specific CD8 T cell and their expression
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infections. Early during the second (meningo- of α4-integrin and β1-integrin. Almost all of
encephalitic) phase of TBE, CSF contains a the TBEV-specific CD8 T cells from peripheral
higher proportion of neutrophils, whereas blood express α4-integrin and β1-integrin
mononuclear cells steadily increase overtime early during second phase of TBE (1 and 3
47
to become the dominant cell type. weeks), whereas the bulk CD8 T cells
Importantly, immune cells such as CD4 and expressed lower levels of integrins. Expression
CD8 T cells, NK cells and B cells are also of α4β1 is associated with the ability to
present in the CSF of TBE patients, with T cell infiltrate tissues and cross the BBB. 88-91 The
frequencies being higher than in blood, same study, however, did not detect higher
indicating selective migration of these cells CXCR3 expression on TBEV-specific CD8 T cells
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through the BBB. Most previous studies on as compared to bulk CD8 T cells. This may be
CNS infiltration of T cells, however, were due to the majority of TBEV-specific CD8 T
performed in human neuroinflammatory cells residing in the CSF during patient
diseases and in animal models for auto- sampling or by the possibility that CXCR3 is
immune and viral infections, including HIV. 88-92 not crucial for CD8 T cell migration across the
BBB in TBEV-infection. Further investigations
In general, virus-specific effector T cells are on the mechanism for T cell migration into the
recruited to the CNS during infections by
88-90,92 CNS during TBE are required in order to
chemokines and integrins. To date, the
explain the local CNS pathogenesis of this
exact mechanism for the recruitment of T cells
disease.
(including TBEV-specific T cells) into the CNS
during TBE is not clear, however certain
chemokines and chemokine receptors were
suggested to be involved. For example, Host factors and TBE disease
infiltrating CCR5 and CXCR3-expressing T cells As for most human infections, the clinical
seem to have a role in TBE in humans (Figure
outcome of TBE is extremely variable, ranging
3). Chemokine CXCL10 (ligand for CXCR3) and from asymptomatic to lethal. A more severe
CCL5 (ligand for CCR5) levels in the CSF of TBE TBE is associated with increased age, severity
patients are increased together with higher of symptoms during the first (febrile) phase,
CCR5 expression on infiltrated CD4 T cells as low neutralizing antibody titers at onset and
compared to blood. 80,81,84 Interestingly, a low early CSF IgM response (as reviewed in ).
1
mutation in CCR5 is associated with a more The risk of developing TBE after exposure to
severe course of the disease. 36,93
the virus may also vary between individuals.
For instance, an epidemiological study in

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