Pathogenesis of tick-borne encephalitis

Incubation period and primary replication

The pathogen enters the body through the portal of entry, which depends on the route of infection. In the primary transmissive route, the virus enters through microtraumas of the skin during a tick bite. In alimentary infection (consumption of raw milk from infected animals), the portal of entry is the mucous membrane of the gastrointestinal tract, as the virus is able to overcome the gastric acid barrier.

Primary accumulation of viral particles occurs strictly in the site of entry:

• In a bite — in the endothelial cells of blood and lymphatic vessels of the subcutaneous adipose tissue and dermis.
• In the alimentary route — in the epithelial cells and lymphoid structures of the digestive tract.

Following primary replication, the pathogen enters the bloodstream. The viremia phase begins: the virus is disseminated throughout the body, forming secondary replication foci in macrophages and the endothelium of internal organs, which concurrently causes sensitization of immunocompetent cells.

Period of clinical manifestations and invasion into the CNS

Active replication in secondary foci leads to a sharp increase in viremia and the development of a pronounced cytopathic effect. The body reacts with a systemic inflammatory response: macrophages, neutrophils, and lymphocytes are activated, and there is a massive release of inflammatory mediators and cytokines. Immune-mediated cytolysis develops, which clinically manifests as a severe intoxication syndrome.

The pathogen penetrates the central and peripheral nervous system via three routes:

1. Hematogenous
2. Lymphogenic
3. Perineural

Neurotropic strains of the virus (whose virulence is largely associated with the envelope glycoprotein E) actively replicate in neurons and glial cells. This is precisely what causes the appearance of focal and meningeal neurological symptoms. During this same period, the immune system begins to produce specific IgM class antibodies.

Pathomorphological changes in severe forms

The morphological picture of tick-borne encephalitis is characterized by an extremely diffuse lesion of the nervous system. The pathological process involves the meninges, white and grey matter, peripheral nerves, and roots. This symptom complex is defined as panencephalitis or meningo-encephalo-myelo-radiculoneuritis.

Two main types of morphological changes are distinguished:

• Vascular (predominant): pronounced edema, perivascular cell infiltrates, erythro- and leukostasis, hemorrhages.
• Neuronal: nuclear disintegration, pyknosis, neuronophagia phenomena, and irreversible neuronal dropout.

The topography of lesions has a clear hierarchy by severity (in descending order):

1. Anterior horns of the cervicothoracic segment of the spinal cord (affected most severely and consistently, with the intensity of changes decreasing toward the lumbar segment).
2. Subcortical ganglia and diencephalic structures.
3. Cerebellar cortex.
4. Cerebral cortex (involved to the least extent).

Outcomes, persistence, and chronic progression

The convalescence period is accompanied by an increase in immune defense: the synthesis of IgG antibodies starts by the third week from the onset of the disease. However, viral elimination (clearance) occurs very slowly. A prolonged, sometimes lifelong, viral persistence is typical for tick-borne encephalitis even against the background of complete clinical well-being.

The putative mechanism of chronic progression is associated with the ability of proviral DNA to integrate into the host cell genome, which ensures a low replication rate for the infection. This can lead to two variants:

• Development of a progredient (continuously progressing) course.
• Formation of a latent infection, in which the virus is not detected by standard methods.

Latent infection is capable of reactivation with the return of viremia. Reactivation triggers are often stress factors: the use of antibiotics and immunosuppressants, mental and physical trauma, abortions, as well as prematurely initiated physiotherapeutic or sanatorium-resort treatment.

Class and exam questions

What else to study on this topic

• Structure of the TBE virus and properties of surface protein E
• Epidemiology, reservoirs, and vectors of infection
• Clinical classification of acute and chronic forms of TBE
• Features of the course of Far Eastern and Central European subtypes

Other topics in the "Vector-borne infections" section

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