Page 169 - TBE_Book_V2_2019

Chapter 9: Immunology of TBEV infection

Viral dissemination and entry into the Innate immune system and TBE
CNS
The innate immune system
Systemic virus infection – viremia, is a
The primary function of the innate immune
common cause of febrile flu-like symptoms
system of the host is to prevent the entry of
manifesting due to the immune response to a
virus. It is therefore assumed that the first and colonization by pathogenic micro-
phase of TBE involving febrile symptoms is the organisms, and if entry occurs, to limit the
result of immune responses to the systemic infection. All cells in the body, though to a
varying extent, are “trained” to recognize and
infection with TBEV. During this phase, TBEV
RNA can be detected in human blood respond if such penetration occurs. The innate
samples. 10,11 As soon as anti-TBEV antibodies immune cell recognition of pathogens takes
are detectable in the blood, viral RNA can advantage of pattern recognition receptors
usually no longer be found in blood or CSF (PRRs). PRRs detect pathogen-associated
samples. 10,11 TBEV RNA has been detected in molecular patterns (PAMPs) to initiate
urine samples during the second (meningo- protective immune responses and subsequent
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encephalitic) phase of the disease, and elimination of the “invaders”. Different
persistent viremia has been described in classes of PRRs are involved in detection of
immunosuppressed patients. 12,13 viral infections, such as Toll-like Receptors
(TLRs), cytoplasmic protein retinoic acid–

The exact route of TBEV entry into the CNS is inducible gene 1 (RIG-I) and structurally
unknown. TBEV antigen is found in brain related melanoma differentiation-associated
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tissue in autopsies from fatal cases of TBE, and gene 5 (MDA5). Via different signalling
pathways these molecules induce antiviral
the virus is selectively localized in the
3
neurons. As for other, more well-studied responses upon sensing viral PAMPs from
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neurotropic flaviviruses in this context, e.g. different cellular compartments. Endosomal
West-Nile virus (WNV) and Japanese TLRs, for example, including TLR3, TLR7, TLR8
Encephalitis virus (JEV), different ways of viral and TLR9, recognize viral nucleic acids,
including double-stranded RNA, single-
entry have been suggested, that may be 22
dependent on blood-brain barrier (BBB) stranded RNA, and DNA. Upon ligand
breakdown, passive diffusion of virus, or via recognition, TLRs trigger the production of
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infected-leukocytic trafficking. An additional type I interferons (IFN) and inflammatory
mechanism that has been suggested is trans- cytokines/chemokines to activate antiviral
defense mechanisms and to initiate adaptive
neural invasion of virus into the CNS, via either 22
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peripheral somatic or the olfactory nerves. immune responses.
TBEV can infect various cells from the central
nervous system in vitro, including brain Type I IFN can be produced by most cell types
microvascular endothelial cells in a BBB and its receptors are widely distributed on the
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model. 15-18 However, BBB breakdown does not cell surface. Binding of IFNs produced by
seem to be a prerequisite for TBEV entry into infected cells to the IFN receptor complex on
the brain. In vitro studies show that the virus the surrounding cells results in the expression
can cross the BBB via a transcellular pathway of interferon-stimulated genes (ISG). ISGs have
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without altering the BBB integrity. been shown to modulate/inhibit viral replica-
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tion by inducing an antiviral state. In
Additionally, in a rodent TBE model BBB
breakdown is primarily a result of cytokine addition to interferons, cytokines and
release by the infected cells and BBB chemokines are also very important secreted
breakdown is not required for TBEV entry into factors of the immune response to patho-
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19 gens. They orchestrate many processes
the brain.
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