Page 172 - TBE_Book_V2_2019

Chapter 9: Immunology of TBEV infection

during infection by controlling immune cell In vitro experiments demonstrate that
trafficking and determining the nature of the astrocytes initiate a very early type I IFN
downstream immune responses. Important antiviral response upon TBEV-infection
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cells of the innate immune system are thereby limiting viral replication and spread.
dendritic cells (DCs), phagocytes (neutrophils, RIG-1-like receptors are upregulated together
monocytes and macrophages), cells releasing with various ISGs in human neuronal derived
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inflammatory mediators (basophils, mast cells cell lines by TBEV-infection. A number of
and eosinophils) and the NK cells. ISGs have been shown to specifically target
TBEV-infection. The Tripartite motif (TRIM)
As the innate immune system is activated 79α protein restricts TBEV and Langat virus
during the early stages of infection, it is replication by mediating lysosome-dependent
difficult to study its role in TBEV-infection in degradation of the NS5 protein. TRIM79α
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humans. TBE patients are usually admitted to was also important for eliciting antiviral
hospital very late during the infection, already activity of IFNβ for inhibition of TBEV
after the adaptive immune system responses replication. Viperin (virus-inhibitory protein,
are initiated. Therefore, the majority of endoplasmatic-associated, interferon in-
research on TBEV and the innate immunity are ducible) has also been shown to restrict TBEV
performed in mouse and in vitro models, also replication by proteasome-dependent de-
taking advantage of the natural attenuated gradation of NS3 viral protein, and reduced
Langat virus that belongs to the TBEV the stability of other TBEV proteins (prM, E,
serocomplex. NS2A and NS2B) in the presence of NS3.
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Studies of polymorphisms in innate immune

genes support the importance of innate
Pattern recognition receptor immunity in TBE, as 5 different single
nucleotide polymorphisms (SNPs) in the
signalling and type I interferon interferon-induced antiviral proteins oligo-
response to TBEV
adenylate synthetase 2 (OAS2) and 3 (OAS3)
As for other viral infections, animal models have been suggested to be associated with
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and in vitro experiments demonstrate that clinical TBE infection.
type I IFN has a protective role against TBEV- Even though TLR signalling has been studied to
infection. IFN-receptor-deficient mice infected some extent in other flavivirus infections ,
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with TBEV or Langat virus develop severe the role of TLR in TBEV infection is not clear. A
clinical symptoms and succumb to the functional TLR3 receptor was suggested to be
infection, most likely due to unrestrained a risk factor for clinical TBE infection in adults,
systemic viremia, and local inflammation but not in children. 34-36 TLR7 signalling has also
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induced by viral replication in the brain. been shown to have a role in controlling the
Further experiments have suggested that replication of Langat virus as TLR7-deficiency
interferon-beta promoter stimulator 1 (IPS-1), in mice increases the virus burden in the CNS.
a downstream adaptor for MDA5 and RIG-1- However, increased viral burden does not
like receptor signalling is important in seem to influence the level of neuro-
controlling TBEV and Langat virus infection in pathogenesis. The mechanism for the
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mice. Knockout of IPS-1 leads to increased increased viral replication in the neurons of
viral replication, release of inflammatory these TLR7-deficient mice is not clear.
cytokines and immune cell infiltration in the However, lower levels of pro-inflammatory
CNS of Langat infected mice. cytokines and chemokines is observed.

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