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Chapter 4: Pathogenesis of TBE

protect mice from lethal infection. In the TBEV proteins; prM, E, NS2A, NS2B and NS3.
absence of this response, the virus replicates The interaction between NS3 and viperin
uncontrollably in all organs, induces a rapid results in proteasome-dependent degradation
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opening of the blood-brain barrier, and the of NS3. The stability of prM, E, NS2A and
mice succumb very quickly. This research has NS2B are affected by viperin, but only in the
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also shown that IFNAR is important in all cell presence of NS3. Interestingly, although
types; hematopoietic, stroma, neuro- viperin does not directly interact with the
5
ectodermal and cells in the periphery. TBEV C protein, viperin expression induces C
particle formation and release from virus
Most steps in the viral “life” cycle are targeted infected cells and disturbing the assembly
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by 1 or several antiviral proteins encoded by process of TBEV. Viperin mediates this effect
the ISGs. Although several ISGs have been by interacting and sequestering the cellular
screened against TBEV (Figure 3), only 2 have protein Golgi brefeldin A-resistant guanine
been identified to be antivirally active so far; nucleotide exchange factor 1 (GBF1), which
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the rodent tripartite motif (TRIM) protein, is involved in the vesicular trafficking of the
TRIM79α, and viperin (virus inhibitory protein, secretory pathway 48,49 and is a pro-viral factor
endoplasmic reticulum-associated, IFN- for many different viruses. 50-53 Thus, viperin
inducible). 40,41 The antiviral mechanism of may target other viruses via its interaction
TRIM79α is direct targeting of the viral with GBF1. The in vivo importance of viperin
polymerase, the non-structural protein 5 during TBEV infection was recently shown in
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-/-
(NS5), an essential component of the the viperin mice. This study shows that
replication complex, for lysosomal degrada- specific regions of the brain rely differentially
tion. TRIM79α seems to be specific for TBEV on the antiviral activity of viperin for
and LGTV, because mosquito-borne flavi- protection against LGTV. Viperin is important
viruses; WNV and Japanese encephalitis virus in the olfactory bulb and cerebrum, while viral
(JEV), were shown not to be restricted by this replication was unchanged in cerebellum and
40
protein. Viperin, on the other hand, is a brain stem in the absence of viperin. This
highly conserved protein with broad spectrum effect is due to the different neuronal sub-
antiviral activity, which has been shown to types, viperin expression is very important in
restrict a diverse range of viruses from cortical neurons but not at all in granular cell
different families. For the Flaviviridae family, neurons isolated from the cerebellum.
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viperin restricts hepatitis C, DENV, WNV and Although only 2 antiviral proteins have been
TBEV. However, the antiviral mechanism identified so far, there are likely several others
seems to depend on the specific virus. For that are involved in the restriction and
TBEV, viperin selectively targets the positive protection against TBEV and LGTV in vivo. One
stranded RNA synthesis. The intracellular of the difficulties in identifying antiviral ISGs
location to the ER via viperin's N-terminal might be the redundancies seen between
amphipathic alpha helix is important as it different proteins.
coincides with viral replication. The antiviral
activity is depending on the radical S-adenosyl Even though different ISGs can potently
methionine (SAM) domain and the proper iron restrict TBEV replication if induced before
-sulphur maturation of the protein. 41,42 Recent infection, 40,41,54,55 IFN treatment after infection
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studies have identified several viral and has limited effect in vitro. The reason for this
cellular interaction partners to viperin. 42-47 is the expression of an IFN antagonist,
Viperin is able to target TBEV in multiple ways NS5. 55,56 The NS5 protein of LGTV interferes
mediating antiviral activity in a cell type- with the phosphorylation of Jak1 and Tyk2 in
specific manner. Viperin interacts with several response to IFNβ, which leads to failure of

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