Page 173 - TBE_Book_V2_2019

Chapter 9: Immunology of TBEV infection

Innate response and its antagonism Innate cellular responses in
by TBEV circulation during TBE

Many viruses induce activation of PRR and
subsequent IFN signalling within hours of viral NK cells
infection. Similarly to other viruses, TBEV may
Natural killer (NK) cells are cytotoxic innate
also have many mechanisms to interfere with
or evade the innate immunity. TBEV as a single lymphoid cells that are an important part of
-stranded RNA (ssRNA) virus produces double- the immune response against viruses and
tumor cells. NK cells represent a distinct
stranded RNA (dsRNA) intermediates during
population of lymphocytes that lack CD3 and
replication. One of the earliest immune
express CD56. The two main NK cell
evasion strategies by TBEV is to hide its dsRNA
from the cytoplasmic PRRs within the host populations in peripheral blood of healthy
dim
+
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cells by rearranging internal cell membranes. individuals are the cytotoxic CD56 bright CD16 NK
-
cells, and the less cytotoxic CD56 CD16 NK
Inaccessibility of dsRNA for cytoplasmic PRRs
cells which produce larger amounts of
delays the activation of interferon regulatory 42
factor 3 (IRF-3), a key transcriptional regulator cytokines upon activation. The ability of NK
of type I IFN response. This results in a cells to distinguish between normal and
subsequent 24h delay of IFN production giving infected cells is partly dependent on the
surface MHC class I expression levels. In
an opportunity for TBEV to replicate
38
unhindered. addition, NK cells express multiple activating
and inhibitory receptors, and the state of NK
Effective and early IFN responses are critical activation or tolerance is dependent on a
balance of the engagement of these
during viral infection, thus active antagonism 43
receptors. NK cell cytotoxicity is mediated
of host proteins involved in IFN responses is
via three main pathways: 1) cell lysis of
another common viral mechanism of evasion.
Viruses often use their own proteins to infected cells using perforin- and granzyme, 2)
directly interact with and inhibit IFN signalling Fas ligand–mediated induction of apoptosis, 3)
antibody-dependent cellular cytotoxicity, NK
molecules. Studies on Langat virus have
cells also produce cytokines and chemokines
shown that viral nonstructural protein 5 (NS5)
for communication with surrounding cells,
is an IFN antagonist and inhibits the JAK-STAT
signal transduction pathway by blocking the thereby also bridging the innate and adaptive
44
phosphorylation of STAT1, STAT2, Tyk2 and immune response.
39
Jak1. Similarly, TBEV NS5 protein was also
In patients suffering from TBE, NK cells are
found to block the phosphorylation of STAT1
by binding to the host membrane protein present in both peripheral blood and the CSF
scribble (hScrib) resulting in inhibition of with higher percentages of NK cells residing in
45
40
downstream IFN signalling. Another known the blood. Even though the virus is not
detected during the second phase of TBE,
target of TBEV NS5 is host protein prolidase
increased levels of cytokines that either
(PEPD). Interaction of NS5 with PEPD is
associated with decreased surface expression activate or are produced by NK cells are
46
of type I IFN receptor subunit IFNAR1 resulting detected in blood. In addition, NK cells are
41
in reduced ISG expression. These findings shown to be activated at early time points
during the second phase of TBE (Figure 2). The
highlight an important role of TBEV NS5
TBEV-induced NK cell activation was
protein as a strong antagonist of type I IFN
response. predominantly seen in more differentiated NK
+
dim
cells (CD57 CD56 ). The activated NK cells
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