Page 99 - TBE_Book_V2_2019

Chapter 4: Pathogenesis of TBE

STAT1/2 phosphorylation and subsequent ISG viruses for phagocytosis and destruction by
expression. 55,56 Werme et al showed that the macrophages. 58,59
interaction between Scribble and NS5 is
important for plasma membrane targeting and Stimulation of all complement activation
IFN antagonist activity; however, the exact pathways contributes to protection against
56 flaviviruses. For WNV infections enhanced
target of NS5 is unclear. In addition, NS5 was
shown to block IFN signaling by selectively susceptibility was shown for mice deficient in
reducing the level of IFNAR1 expression on the various components of the complement
cell surface. This reduction was dependent on system. Less is known about the complement
NS5 binding to prolidase. Prolidase is needed activation during TBEV infection. Antibody-
for IFNAR1 intracellular trafficking, matura- dependent, complement-mediated cytolysis of
tion, activation of IFNβ-stimulated gene infected cells is considered a possible
induction, and IFN-I-dependent viral control mechanism of protection by NS1 antibodies,
60
57
(Figure 4). The relationship between NS5 since NS1 is expressed on the cell surface. In
function and virulence has not been observed response to these protective functions, many
for tick-borne flaviviruses, such as TBEV and viral pathogens have evolved evasion strate-
the low virulence LGTV NS5; both exhibited gies to limit recognition by and activation of
the same degree of p-STAT inhibition. the complement cascade. NS1 proteins of
However, there are most likely other viral different flaviviruses limit complement
proteins that are important for pathogenicity activation by forming complexes with C1s and
and suppression of innate immune responses, C4 to promote cleavage of C4 to C4b. Another
as this has been shown for other flaviviruses. mechanism shows direct interaction of NS1
However, for TBEV these mechanisms have with C4b binding proteins which leads to
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yet to be identified. reduced C4 activity. Although these inhibito-
ry mechanisms are functional in various

flavivirus strains, less is known about the role
of NS1 protein from TBEV.
Complement

The complement system plays an essential
role in the innate immune responses to many Innate and adaptive immune
pathogens including flaviviruses. There is interface
growing evidence that the complement
system participates in the adaptive immune Natural killer (NK) cells
response. More than 30 proteins and protein
fragments form a network of soluble and cell Natural killer (NK) cells are large granular
surface proteins that recognize and target lymphocytes that play an important role in the
pathogens. They orchestrate three distinct control of viral infections. NK cells limit viral
cascades: the classical pathway, alternative replication by killing infected cells during early
pathway, and lectin pathway. Each comple- stages of infection. The antiviral response of
ment activation pathway is initiated by a NK cells includes direct killing of virus–infected
distinct set of recognition molecules and cells, which is primarily mediated by perforin
converges at the cleavage of C3 to C3a and and granzyme, as well as the production of
C3b. Beyond its lytic capacity, complement several proinflammatory cytokines, including
protects against viral infections by priming IFN-γ and tumor necrosis factor (TNF). These
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adaptive B and T cell responses, triggering molecules are components of the innate
leukocyte chemotaxis through the release of immune response as they are activated by
anaphylatoxins (C3a and C5a), and opsonizing

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