Page 102 - TBE_Book_V2_2019

Chapter 4: Pathogenesis of TBE

Other data suggest that T cells within the CNS Recently we used C57BL/6 mice to
promote survival. In CCR5-deficient mice, an characterize TBEV pathogenesis. Two different
increase of viral replication in the CNS and strains showing different symptoms are
decreased survival is due to the lack of investigated. Namely HB171/11, isolated from
lymphocyte migration to the CNS. Adaptive questing adult ticks from a natural focus in
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transfer of LGTV-specific T cells improved south Germany and Torö-2003, rescued from
survival outcome. However, whether the a cDNA infectious clone generated from RNA
protective effect is only mediated by T cells or extracts of nymphs collected in the island of
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by the decrease of inflammatory neutrophils Torö, Sweden. Both strains showed highly
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in the presence of T cells is not clear. different symptoms in humans, as HB171/11
Because TBEV-infected mice also died of leads to mild gastrointestinal and constitu-
encephalitis in the absence of T cells, other tional symptoms without affecting the
cells such as neutrophils could contribute to nervous system. TBE cases in the region of
pathogenic effects of TBEV infection. Further Torö showed relatively mild neurologic
investigation is needed to better understand disease and few cases of hospitalization. The
the processes that control the protective infection of mice reflects the different course
rather than pathogenic CD8+ T cell response of infection in humans, we observed lower
during TBEV infection. pathogenicity of HB171/11 in comparison to
Torö-2003 infections. Torö-2003 replicates

faster in the periphery and enters the brain
Tools to study pathogenesis very early during infection. In addition,
neurovirulence was lower in HB171/11-
infected mice. The mechanism of virulence
Mouse models
and neuropathology is still under investiga-
tion, although differences in cytokine
Laboratory mice are a useful tool to
investigate human diseases, as mice are induction and viral replication in target cells
phylogenetically related to humans and show could be involved. In summary, mouse models
a striking genomic homology. This is especially could be a good tool to contribute to our
true with knockout mice, in which an existing understanding of pathogenesis of TBEV
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gene is inactivated. Laboratory mice are used infection.
to better understand how a similar gene in Reverse genetics systems
humans may cause or contribute to disease.
The mouse as a model system for studying Reverse genetics of viruses is the generation
pathogenesis of TBEV has an advantage and manipulation of viral genomes to
compared with other flaviviruses, because
investigate the direct effects of changes on
mice are susceptible to natural TBEV isolates, virus biology and pathogenesis. For
and develop encephalitis, whereas other flaviviruses, the first reverse genetic system
flaviviruses require mouse adaptation to cause was developed in 1989 for YFV. Since the
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disease.
genome of flaviviruses is positive stranded,
Animal models of TBEV infections have they are infectious if introduced into
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provided insights into the pathogenesis of TBE susceptible cells. There are several different
in humans. In particular, TBEV and LGTV approaches to generate infectious virus. One
important step is the generation of a
infections of mice enable the identification of
complimentary DNA (cDNA) to the RNA
host and viral genetic factors that contribute
to the outcome of infection, as shown through genome. The cDNA is often cloned into a
the studies described elsewhere and in this plasmid under a specific promoter, which
enables the in vitro transcription of viral RNA.
chapter.
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