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Chapter 4: Pathogenesis of TBE

adaptive immune response that reacts to mechanisms of CNS invasion by neurotropic
infection. The innate immune response viruses are breakdown of the BBB, infection of
includes cell intrinsic defense mechanisms like cerebral endothelial cells, virus shedding from
apoptosis, autophagy, type I interferon (IFN) choroidal cells, axonal transport through
response, and innate cell-mediated responses, olfactory receptor neurons, and retrograde
which are then followed by adaptive immune transport along peripheral nerve axons, or
responses with a specific antibody response transport by the “Trojan-horse” mechanisms
and stimulation of T cells that limit virus by which virus is transported by infected cells.
replication and which are involved in Although this process has been studied inten-
6
pathogenicity. If the virus overcomes the sively for West Nile virus (WNV) infection , it is
second barrier, it will spread to peripheral not known how TBEV reaches the CNS, but
organs and cause viremia. The third barrier breakdown of the blood-brain barrier is
controls entry of the virus to the central unlikely because virus replication is detectable
5,7
nervous system (CNS), e.g., by the blood-brain in the brain before BBB disruption.
barrier (BBB). If overcome, the virus will

replicate in neurons and cause encephalitis
and meningitis.
Cellular responses to TBEV and
Initial infection, viral amplification, implications for pathogenesis
and spread
Cell-intrinsic innate immunity
Very early during the tick feeding process
TBEV particles are transmitted to the host via All cells have the capacity to react to various
tick saliva. Tick saliva acts as a pharmaco- stresses, such as starvation, temperature
logically active compound which inhibits pain/ extremes, irradiation, and infection. Cell-
itch response, contains anticoagulants, anti- autonomous protective programs, which are
platelet components, vasodilators, and inherent in all cells of the body are termed
1,2
immunomodulators, that enhance viral intrinsic cellular defenses.
3
transmission and dissemination. Analysis of Autophagy
skin explants from tick-feeding sites reveals
viral antigen in neutrophils, monocytes and Autophagy is a degradation pathway that
4
skin-resident dendritic cells (DC). Although occurs under stress conditions such as
not proven, these cells are likely to serve as a
starvation, hypoxia, and infection. It starts
vehicle for transport of the virus to draining with the sequestration of the area of the
lymph nodes. For other flaviviruses it was cytoplasm inside double-membrane vesicles
demonstrated that viral amplification in the
called autophagosomes, which subsequently
lymph nodes results in viremia and spreads to fuse with lysosomes to form autolysosomes or
peripheral tissues. The specific target cells for late endosomes. Dengue virus (DENV)
8
TBEV infection in peripheral tissues are not infection promotes the formation of
well defined, but are thought to be subsets of autophagy, which can enhance virus repli-
5
DCs, macrophages and possibly neutrophils.
cation and protects cells against other
stressors. 9,10 Inhibition of dengue-induced
Neuroinvasion
autophagy by pharmacological inhibitors or
deficiency of autophagy-related genes (ATG)
TBEV is a neurotropic virus and neuro-
reduces dengue replication. The importance of
pathogenesis depends on the ability of the
virus to enter the CNS and propagate. General autophagy during TBEV replication was shown
by stimulation of autophagy which results in

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