Discovery history and virion morphology
TBEV was discovered in 1937 in the Far East by an expedition led by L.A. Zilber. The pathogen was isolated from the brains of deceased patients, the blood of sick individuals, as well as from ticks and wild vertebrates. It was the first pathogenic virus discovered in the Russian Federation, marking the beginning of domestic arbovirology.
Taxonomically, the pathogen belongs to the family Flaviviridae (genus Flavivirus) and is a typical representative of the tick-borne encephalitis complex. The virion has a lipoprotein envelope enclosing a single-stranded positive-sense RNA. Among the structural proteins, the key one is surface glycoprotein E (dimer). It determines cell tropism, carries determinants of viscerotropism and neurovirulence, and acts as the primary immunogen (inducing virus-neutralizing antibodies). Non-structural proteins (NS1–NS5) and viral RNA polymerase are responsible for replication.
Variability and resistance
The virus exhibits high geographical and intra-population variability. Three main antigenically distinct genotypes are distinguished:
- Far Eastern.
- European.
- Ural-Siberian.
Despite these differences, structural protein E induces cross-immunity common to all virus variants.
In the external environment, TBEV has low resistance to physical and chemical factors. However, within the vector's body, it survives across a vast temperature range (from –150 to +30 °C). An important clinical feature is resistance to an acidic environment, which allows the virus to bypass the gastric barrier during the alimentary transmission route.
Epidemiology: reservoirs and transmission routes
The main reservoirs and vectors are ixodid ticks: the taiga tick (Ixodes persulcatus) and the castor bean tick (Ixodes ricinus). The virus actively replicates and persists for life within their bodies (in the gastrointestinal tract and salivary glands). Ticks transmit the pathogen transstadially (during molting from larva to nymph and adult) and transovarially (via eggs to offspring). Warm-blooded animals and birds are required as hosts to maintain the virus population.
Humans (a biological dead-end for the virus) become infected through three routes:
- Transmitted by vector: via blood-feeding or crawling of an infected tick.
- Contact: through microtraumas of the skin, for example, when crushing a tick with hands.
- Alimentary: through the consumption of raw goat and sheep milk, leading to the development of biphasic meningoencephalitis ("milk fever").
Pathogenesis and clinical forms
The incubation period lasts from 8 to 28 days. Pathogenesis has visceral and neural stages. Following primary replication at the site of entry, the virus enters the bloodstream (viremia), settling in the lymph nodes, spleen, and vascular endothelium. Secondary viremia lasts about 5 days and coincides with the onset of fever and intoxication.
CNS damage occurs via hematogenous and, likely, perineural pathways. The pathogen selectively attacks large motor cells of the anterior horns of the spinal cord and the cranial nerve nuclei of the brainstem. The accumulation of the virus causes necrosis of these motor neurons, which clinically manifests as flaccid paresis and paralysis.
The following forms of acute course are distinguished:
- Febrile (abortive) — favorable outcome.
- Meningeal — favorable outcome.
- Focal (paralytic) — includes meningoencephalitic, poliomyelitic, and polyradiculoneuritic subtypes. Mortality reaches 15–20%, and consequences include persistent paralysis and contractures.
Chronic progression and slow infection
In 2–12% of cases, the disease acquires a progressive course. TBEV acts as a facultative pathogen of slow infections. Chronic progression occurs against the background of active antibody synthesis, which cannot protect the organism.
The persistence mechanism lies in the fact that the virus "hides" intracellularly: it does not express its antigens on the cell membrane and causes no cytopathic effect (CPE). Thus, the infected cell escapes immune surveillance. The course can be primary-progressive (without a clear acute phase) or secondary-progressive.
Diagnostics and prevention
The diagnosis is confirmed by isolating the pathogen (in cell cultures or via intracerebral inoculation of mice), serologically (titers rise in complement fixation test [CFT], hemagglutination inhibition test [HIT], detection of IgM via ELISA in the 1st week), and rapid methods (PCR of blood, CSF, or the tick itself).
Etiotropic therapy consists of administering human immunoglobulin or immune plasma strictly during the first days of the disease (no later than the 3rd–4th day).
Prevention:
- Emergency: administration of immunoglobulin in the first 96 hours after a bite from an infected tick. Important: after the 4th day, administering antibodies is strictly prohibited due to the risk of antibody-dependent enhancement (ADE) of the infection, which worsens the disease.
- Routine (vaccination): administration of killed cell-culture vaccines to residents of endemic zones.
- Nonspecific: boiling milk to interrupt the alimentary transmission route.
Briefly: answers to topical questions
What structural proteins make up the tick-borne encephalitis virion?
The tick-borne encephalitis virion contains three types of structural proteins.
- Capsid protein (C).
- Membrane protein (M).
- Surface protein E — a dimer, the key virion protein. It determines cell tropism, carries virulence determinants, including viscerotropism and neurovirulence, and serves as the main immunogen inducing virus-neutralizing antibodies.
In which cells and tissues does primary replication of the tick-borne encephalitis virus occur before the development of viremia?
Primary replication of the tick-borne encephalitis virus before the development of viremia occurs directly at the site of its entry (portal of entry). Depending on the transmission mechanism, replication and accumulation of the pathogen take place in the following tissues:
- Skin and subcutaneous adipose tissue — replication occurs in the endothelium of blood and lymphatic vessels (during percutaneous penetration via tick bite or microtraumas).
- Gastrointestinal mucosa — the virus replicates in the epithelium and lymphoid formations (during alimentary transmission).
Which specific commercial vaccines are used for routine prevention of tick-borne encephalitis?
For routine specific prevention of tick-borne encephalitis, killed cell-culture vaccines are used. Vaccination is indicated for residents of endemic zones and individuals traveling there during the spring-summer season.
Specific commercial vaccines mentioned in the sources include the Encepur series.
The clinical triad of the virus can be remembered by the acronym FACE: F — Fever, A — Intoxication (altered state/toxicosis), C — Central nervous system (CNS involvement).
Class and exam questions
Can one contract tick-borne encephalitis without a tick bite?
Yes. Infection is possible through the consumption of raw milk from infected goats or sheep (alimentary route), as well as when the virus enters microtraumas in the skin from crushing a tick.
Why is emergency seroprophylaxis administered only within the first 4 days?
Administration of preformed antibodies later than 96 hours after a bite (during the incubation period) is prohibited. This is due to the risk of antibody-dependent enhancement of infection, where antibodies facilitate viral entry into target cells, sharply worsening the disease.
How does the virus survive in the body during the chronic form in the presence of antibodies?
The virus remains strictly intracellular, causes no cell death (cytopathic effect), and does not display its protein antigens on the cell surface. Consequently, the immune system fails to recognize the infected cell.
What else to study on this topic
- Molecular mechanism of antibody-dependent enhancement (ADE) of infection
- Biphasic meningoencephalitis: immunological causes
- Structure and functions of flavivirus non-structural proteins (NS1–NS5)
- Differences between tick-borne encephalitis vaccines and immunization schedules
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