Tick-borne encephalitis pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

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Overview

Tick-borne encephalitis is caused by a (+)ssRNA virus of the Flavivirus genus. Three subtypes of the virus exist including the Far East, European, and Siberian subtypes. The Ixodidae family of ticks is the primary vector associated with transmission, with other modes of transmission including the consumption of unpasteurized, raw milk. Pathogenesis occurs as the virus binds to a host cell receptor. Through a series of reactions, the virus enters the cell, is translated, and hi-jacks the host cell's replication machinery. After which immature virions are released within the cell, to ultimately spread infection. Viral replication will often occur within subcutaneous tissue. Replication also occurs within the lymph nodes, causing immense damage to the immune system. A later phase of the virus results in an infection of the CNS as the immune response increases the permeability of the blood-brain barrier.

Transmission

• The Ixodidae family of hard ticks have been reported as the vector and reservoir of the Tick-borne encephalitis virus.
• Other modes of transmission include the consumption of raw milk as well as vertical transmission from mother to fetus.

Virology

• Member of the Falvivirus genus
• Flaviviridae family
• Three subtypes: Far East, European, and Siberian
• Viral strains are mostly homogeneous within infected European tick populations.
• Diversity exists within viral strains carried by Siberian and Far Eastern tick populations. Thus these populations host antigenic variations and a variety of subtypes.
• However the antigenic similarity within these populations allows for a generalized protection method among the different subtypes.

Genomics

• (+)ssRNA genome enclosed in a capsid protein.
• Genome is protected by a lipid bilayer, provided by the host or target cell.
• Virus's physical attributes include a spherical particle with an approximate diameter of 50-60nm.
• The genome lacks a 3'-poly(A) tail, yet provides a 5' cap.
• In terms of length, the genome spans an average of 11kb.

Pathogenesis

• The process begins as the virus binds to a host cell receptor.
• A host cell will internalize the virus using endocytosis.
• Post-endocytosis, acidification of the viral envelope causes conformation changes of the E protein, resulting in the attachment of the viral envelope to a endosomal vesicle.
• Once properly mounted on the endosomal vesicle, the viral envelope will release the viral nucleocapsid into the surrounding cytoplasm.
• Translation of the virus yields a 3414 amino acid long polyprotein.
• The polyprotein is cleaved by both cellular and viral proteases.
• The cleaving process results in three structural proteins called C, prM, and E as well as seven non-structural proteins.
• The C protein forms a virion nucleocapsid through binding to viral DNA.
• The E protein is necessary as a ligand to cell receptors and as a fusion protein.
• The other non-structural proteins serve as proteases, polymerases, complement binding antigens, or function within the replication process.
• Finally the processes concludes as the positive-stranded genome is translated while the negative-strand of RNA provides grounds for the RNA replication process.
• Assembly of the virus occurs within the endoplasmic reticulum.
• Post-assembly immature virions are released within the cell.

Schematic drawing of the steps during TBE virus infection. (1) TBE virus transmission from an infected tick, (2) TBE virus replication in regional lymph node, (3) primary viremia, (4) replication of the virus in other organs and tissues, (5) secondary viremia, (6) TBE virus crossing of the blood-brain barrier, and (7) virus infection of the brain]]

Viral pathway within a mammalian host

• Virus replication commonly occurs within subcutaneous tissue.
• Dendritic cells transport the virus to the lymph nodes.
• The virus replicates at a high rate within the lymph nodes, further travelling into the bloodstream.
• Lymphocytes suffer great reductions due to infection with the regional lymph nodes.
• Further infection of external tissues occur within the viremic phase
• The later phase results in the infection of the CNS.
• Furthermore a host's immune system will add to the severity of the infection, as resulting immune response includes inflammation CD8+ T-cells infiltrating the brain.
• Other immune responses such as the upregulation of proinflammatory cytokines increase the permeability of the blood-brain barrier.