Page 96 - TBE_Book_V2_2019

Chapter 4: Pathogenesis of TBE

Recognition of TBEV and induction of Kinase 1 (TBK1) and Inhibitor-κB kinase ε
IFN (IKKε) are recruited, leading to
phosphorylation and activation of the
Rapid detection of the pathogen is crucial for transcription factor IFN regulatory factor 3
mounting a protective response, and several (IRF3). Phosphorylated IRF3, dimerizes and
different PRR families have been identified translocates into the nucleus where it binds to
that recognize numerous ligands. The Toll-like the IFNβ gene promoter to initiate transcript-
31,32
receptors (TLRs) are located on the endosome ion and translation. IFNβ induction after
or the plasma membrane, and the retinoic- TBEV infection has been shown to be highly
acid-inducible gene I (RIG-I)-like receptors dependent on IRF3 activation in the cells, and
(RLRs) are in the cytosol. RNA viruses are most IRF3 has been shown to dimerize and translo-
28
likely recognized by TLR3, TLR7, TLR8, or the cate into the nucleus after TBEV infection.
RLRs RIG-I and melanoma differentiation-
Very little is known about the importance of
associated gene 5, (MDA5), which senses
single-stranded RNA (ssRNA) or double- TLRs in TBEV infection, and only once the TLR7
stranded RNA (dsRNA). 23-25 has been investigated in the context of LGTV
infection in vivo. This report demonstrates
For TBEV, it is not totally clear which PRRs are that mice deficient in TLR7 have higher viral
dominant. RIG-I, which recognizes short load in the CNS and lower levels of pro-
dsRNA and 5’ PPP, has been shown to be inflammatory cytokines. Primary neurons did
important for IFNβ induction in the U2OS not show a difference in infection rate, but
(human osteosarcoma) cell line by siRNA TLR7 deficient neurons induced higher levels
33
26 of IFNβ , indicating that TLR7 is more impor-
depletion, however, the importance of
MDA5 as contributing to sensing of TBEV tant for regulating neuroinflammation than
33
cannot be ruled out as its involvement in type I IFNs.
sensing other flaviviruses has been demon-
27
strated. Both RIG-I and MDA5 bind to the Since the type I IFN response is so important
adaptor mitochondria-associated IFNβ in controlling and restricting viral replication,
most viruses have developed strategies to
promoter stimulator-1 (IPS-1, also called
MAVS, VISA or CARDIF) via its caspase prevent upregulation of IFN by antagonizing
recruitment domain after binding to its RNA the different steps in the IFN induction
ligand. IPS-1 is important for IFNβ induction pathway. For example, dengue virus has been
shown to reduce IFNβ levels by expressing the
after TBEV infection in mouse embryonic 34
protease complex NS2B3, possibly by
fibroblasts (MEFs); in its absence, no IFNβ was 35
28
detected. In addition, mice deficient in IPS-1 cleaving the adaptor STING. Dengue subtype
succumb to LGTV and TBEV infection. These 1/2/4 NS2A and NS4B and West Nile NS4B
mice showed lower systemic levels of IFNα, protein inhibited TBK1 phosphorylation and
36
IFNβ induction. For TBEV, no specific IFN
resulting in higher viral titers in the periphery
20
and leading to rapid invasion in the CNS. IPS- production antagonists have been identified
28
1 is also important in the local IFN response among the different viral proteins. Instead,
within the brain, reducing viral load and TBEV uses a passive escape mechanism that
20,29,30 delays the induction of IFNβ by replicating
spread of LGTV, indicating an especially
inside replication vesicles or packets, thereby
important role for RLR in the type I IFN
hiding its dsRNA from RIG-I and other
response. 26,28,37,38
PRRs. Later, during infection, the
Upon IPS-1 activation, TNF Receptor dsRNA leaks out from the replication vesicles,
Associated Factor 3 (TRAF3), TANK Binding IRF3 is activated and translocates into the
91