Tick-Borne Encephalitis Virus: A Comprehensive Review of Transmission, Pathogenesis, Epidemiology, Clinical Manifestations, Diagnosis, and Prevention

Abstract

Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, can cause serious infection of the central nervous system in humans, resulting in potential neurological complications and fatal outcomes. TBEV is primarily transmitted to humans through infected tick bites, and the viral agent circulates between ticks and animals, such as deer and small mammals. The occurrence of the infection aligns with the seasonal activity of ticks. As no specific antiviral therapy exists for TBEV infection, treatment approaches primarily focus on symptomatic relief and support. Active immunization is highly effective, especially for individuals in endemic areas. The burden of TBEV infections is increasing, posing a growing health concern. Reported incidence rates rose from 0.4 to 0.9 cases per 100,000 people between 2015 and 2020. The Baltic and Central European countries have the highest incidence, but TBE is endemic across a wide geographic area. Various factors, including social and environmental aspects, improved medical awareness, and advanced diagnostics, have contributed to the observed increase. Diagnosing TBEV infection can be challenging due to the non-specific nature of the initial symptoms and potential co-infections. Accurate diagnosis is crucial for appropriate management, prevention of complications, and effective control measures. In this comprehensive review, we summarize the molecular structure of TBEV, its transmission and circulation in natural environments, the pathogenesis of TBEV infection, the epidemiology and global distribution of the virus, associated risk factors, clinical manifestations, and diagnostic approaches. By improving understanding of these aspects, we aim to enhance knowledge and promote strategies for timely and accurate diagnosis, appropriate management, and the implementation of effective control measures against TBEV infections.

Keywords: TBEV; clinical manifestations; diagnosis of TBEV; epidemiology of TBEV; tick-borne encephalitis virus; transmission and circulation in nature.

Figure 1

Genome organization of TBE virus (A) and the schematic representation of produced polyproteins with cleavage products (B). The structural proteins are represented in green, while the nonstructural proteins are in yellow. Cleavage sites for viral serine protease are indicated by black arrows, host signal peptidase cleavage sites by orange arrows, an unknown host protease cleavage site by a blue arrow, and a furin cleavage site by a green arrow.

Figure 2

TBEV life cycle overview. The virus attaches to a receptor on the surface of a cell and enters the cell through endocytosis (1). Once inside the cell, the acidic environment of the late endosome triggers the fusion of the viral and endosomal membranes, leading to the uncoating of the virus (2). The cell ribosomes of the rough endoplasmic reticulum (ER) synthesize viral proteins (3). The virus replicates its genetic material within invaginations induced by the virus in the ER. The newly synthesized genomes are subsequently captured by the C protein on the cytoplasmic side of the ER (4). The nucleocapsid complex, comprising the viral genetic material, obtains structural E and M proteins, along with a lipid envelope, by budding into the ER lumen through the membrane (5). The immature viral particles are transported through the Golgi network where they undergo maturation in the acidic trans-Golgi environment (6). The mature viral particles, partially mature and immature particles, are released from the infected cell (7). While the mature and partially mature particles can initiate a new infection cycle, the immature particles are non-infectious because they are unable to fuse with other cells (8).

Figure 3

TBEV transmission pathways. In vertical transmission, infected ticks pass the virus to their offspring through eggs and across different life stages. Horizontal transmission occurs when uninfected ticks feed on infected vertebrate hosts, but humans are considered dead-end hosts as they do not develop the high levels of viremia necessary for the virus to be transmitted to ticks. In co-feeding, transmission occurs when infected and naïve ticks feed in close proximity on an animal host, which serves as a bridge for virus transmission. This method allows for the fast transmission of the virus among ticks, even if the host has antibodies against TBEV.

Figure 4

Numbers of reported TBE cases in Croatia from 1993 to 2021.