Molecular Structure of Tick-Borne Encephalitis Virus: Comparison
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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. 

  • clinical manifestations
  • diagnosis of TBEV
  • epidemiology of TBEV

1. Introduction

Tick-borne encephalitis virus (TBEV) is a member of the genus Flavivirus and belongs to the family Flaviviridae [1,2][1][2]. In humans, TBEV causes infection of the central nervous system, which can have serious consequences and lead to permanent neurological complications or even death [3,4][3][4]. The morbidity and mortality rates of tick-borne encephalitis (TBE) differ according to the three viral subtypes; namely, European (TBEV-Eu), Siberian (TBEV-Sib), and Far Eastern (TBEV-FE) [3,4,5,6][3][4][5][6]. In addition to the three main subtypes, two recently described subtypes have emerged. The first is the Baikalian subtype (TBEV-Bkl), consisting of 13 strains identified in east Siberia and northern Mongolia [7,8][7][8]. The second is the Himalayan subtype (TBEV-Him), which has been found in wild rodents in the Qinghai–Tibet Plateau region of China [9]. In the last three decades, the spread of TBE has become a substantial concern in Europe and Asia. Notably, there has been an expansion of TBE risk areas into regions that were previously unaffected alongside the emergence of new endemic areas [10,11][10][11]. The incidence of TBEV infections has been steadily increasing, posing a significant and growing health concern [2].

2. An Insight into the Molecular Structure of Tick-Borne Encephalitis Virus

Flaviviruses undergo a maturation process during their production, giving rise to three distinct types of particles within infected cells: immature non-infectious particles, partially mature particles, and fully mature infectious particles [12,13,14][12][13][14]. Mature TBEV particles have a smooth, spherical morphology and are membrane-enveloped with a diameter of approximately 50 nm, similar to those of other Flaviviruses [12,15,16,17,18][12][15][16][17][18]. The icosahedral nucleocapsid, which measures about 30 nm in diameter, consists of several copies of a single viral capsid protein (C) and genomic RNA [13]. The nucleocapsid of TBEV is encased within a membrane. There is a distinction between mature and immature viral particles. Mature viral particles possess an envelope comprising envelope proteins (E) and membrane proteins (M). In contrast, intracellular immature viral particles contain the precursor M protein (prM) in place of the M protein. The prM protein is proteolytically cleaved before the virion is released from the host cell [1]. PrM acts as a chaperone that directs the proper folding of E protein. The envelope E protein creates rod-shaped dimers oriented parallel to the membrane, covering the surface of the viral particle. The mature TBEV particle envelope contains three E proteins and three M proteins in each icosahedral asymmetric unit [12]. The surface of the TBEV virion is adorned with small protrusions, which are created by glycans attached to the E protein subunits. A compact heterotetramer is formed by two E proteins and two M proteins. The envelopes of flaviviruses exhibit a herringbone pattern consisting of three of these heterotetramers [12]. The virus membrane does not have a spherical shape; instead, it closely conforms to the inner surface of the protein envelope. The membrane undergoes deformations due to the insertion of transmembrane helices from E proteins and M proteins [12]. The viral particles are composed of 6% ribonucleic acids (RNA), 66% proteins, 17% lipids derived from host cell membranes, and 9% carbohydrates [1,19][1][19].

2.1. Organization of the Genome

The genome of the virus is a positive-sense single-stranded RNA, approximately 11,000 nucleotides long. Genomic RNA is infectious and is the only viral mRNA present in infected cells [1]. It consists of two short non-coding sequences at the 5′- and 3′- ends and one open-reading frame (ORF), which is approximately 11,000 nucleotides long. After translation and processing of the viral genome, 10 different proteins are produced, three structural (C, prM, and E) and seven nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) [20,21][20][21]. The 5′-short non-coding sequence is approximately 130 nucleotides long and contains a type-I cap (m-7GpppAmp) followed by two conserved AG dinucleotides. The length of the 3′-short non-coding sequence can vary from 450 to 800 nucleotides and it may contain an internal poly-A tail [1,22][1][22]. RNA noncoding sequences create secondary structures that participate as cis-regulatory elements in genome replication, translation, and viral particle assembly [22]. The virus genome has three different roles: (1) as messenger RNA (mRNA) for the translation of viral proteins, (2) as a template for RNA amplification, and (3) as genetic material stored in new viral particles (Figure 1) [23].
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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.

2.2. Viral Proteins

The virus genome is translated into a single polypeptide molecule (~3400 amino acids). The primary translation product is then co-translationally and post-translationally cleaved at specific sites by host and viral proteases. Thus, three structural and seven nonstructural proteins are produced, which participate in virus replication [22,24][22][24]. Host signal peptidases cleave the polyprotein at the C/prM, NS2A/NS2B, NS2B/NS3, NS3/NS4A, NS4A/2K, and NS4B/NS5 junctions. The serine protease of the virus cleaves the polyprotein at the junctions prM/E, E/NS1, and 2K/NS4B [25]. It is not known which enzyme is responsible for cleaving the contact between NS1 and 2A (Figure 1) [23].

2.2.1. Structural Proteins

During polyprotein translation, structural proteins are anchored to the host’s endoplasmic reticulum (ER) with distinct signal sequences and transmembrane domains. The C protein contains a C-terminal hydrophobic signal sequence that translocates the prM protein into the ER lumen. The prM protein contains two transmembrane domains containing stop sequences and a signal sequence. As a result, the E protein is also translocated to the lumen of the ER. In the ER lumen, prM and E proteins form stable heterodimers [26,27][26][27]. Protein C (~120 amino acids, 11 kDa) is a small, strongly basic protein that forms a structural component of the nucleocapsid [23]. The basic building block of the capsid is a dimer of protein C. Each monomer consists of four different α-helices (α1 to α4) connected by short loops [28]. Helices α2 and α4 of one monomer are antiparallel to helices α2 and α4 of the other monomer. All four helices are part of the central hydrophobic domain responsible for interactions within the dimer. It is assumed that the α4-helix, which has a high content of positively charged amino acids, binds non-specifically to viral RNA. At each end of the dimer are two hydrophobic α2-helices that interact with the membrane surrounding the nucleocapsid and are within a groove flanked by the α1-helix [24,28][24][28]. The hydrophobic C terminus of the precursor protein anchors the C protein to the cytoplasmic side of the ER membrane and is an internal signal sequence that allows translocation of the prM protein into the ER lumen. The signal sequence is cleaved in the mature viral particle by the viral protease NS2B-NS3 [29]. Virus multiplication produces complete virus particles and a smaller number of sub-viral non-infectious particles. Deletions or alterations in the amino acid sequence of protein C can lead to the elevated presence of non-infectious sub-viral particles during the assembly of viral particles [29]. It has been observed that the prM and E proteins have the capability to independently assemble sub-viral particles that lack a nucleocapsid [1]. The prM protein (~165 residues, 26 kDa) is the glycosylated precursor of the structural M protein (~75 residues, 8 kDa). In immature viral particles, the prM protein forms heterodimeric complexes with the E protein and thereby protects it by preventing its fusion with the membrane of the trans-Golgi network, which would otherwise occur due to low pH. The prM protein acts as a chaperone for the proper assembly and folding of the E protein [26]. Prior to the release of immature virus particles from the host cell, the prM protein undergoes cleavage by the furin protease (Figure 1). This cleavage event separates the prM protein into two sections: the N-terminal section, known as the soluble ”pr”; and the C-terminal section comprising the structural M protein, which remains anchored to the cell membrane [30]. The M protein consists of a single peripheral membrane helix (h1), two transmembrane helices (h2 and h3), and an N-terminal loop region that engages in interactions with both E proteins. A heterotetramer is formed by two M proteins and two E proteins, wherein each M protein interacts with both E proteins [12]. The heterotetramer functions as the fundamental unit of the mature virion. The N-terminal loop of the M protein interacts with domain II of the E protein, which likely hinders the reorganization of E protein dimers into fusogenic trimers [17]. The E protein (~496 residues, 52 kDa) is the basic envelope protein that covers almost the entire outer surface of the mature viral particle, and it is, therefore, also the primary target of neutralizing antibodies. It is responsible for key functions related to virus entry into cells, such as receptor binding and membrane fusion, and induction of neutralizing antibodies [12,31][12][31]. It is thought that it can attach to several different host cell receptors in both vertebrates and different arthropods (ticks and mosquitoes) [24,32][24][32]. The E protein is an elongated molecule that, before fusion, has the form of a dimer, with the two monomers being oriented opposite to each other (the head of the first faces the tail of the second). On the surface of the virus, the E protein creates a unique so-called herringbone pattern. At low pH, the dimeric form of the E protein dissociates into monomers and then changes irreversibly to the more stable trimeric form [33]. The E protein monomer is comprised of four distinct domains. The N-terminal β-barrel domain (domain I) serves as a central structure within the protein [12,31][12][31]. The extended dimerization domain (domain II) of the mature virus contains the sole glycosylation site (Asn154). It is composed of two regions of β-strands connected by loops and two short helices. In addition to its function in dimerization, this domain also plays a crucial role in egress from mammalian cells and contributes to neurovirulence [34,35][34][35]. Domain II also encompasses the highly conserved fusion loop, which plays a crucial role in mediating the fusion of the viral and host membranes during the final stages of TBEV entry [12,31][12][31]. Domain III exhibits a characteristic immunoglobulin-like shape and has been suggested to play a crucial role in binding to host receptors [31]. Domain IV consists of a stem region comprising three peripheral membrane helices (h1–h3) and a transmembrane region consisting of two helices (h4 and h5) [12]. The connections between the domains are flexible, which is very important in the change from an immature to a mature viral particle, as well as in the process of fusion with the membrane [17,36][17][36]. The C terminus of the protein is anchored to the ER membrane. The transmembrane region of the E protein also plays an important role in the assembly of the viral particle and in the later stages of membrane fusion because it enables the necessary intra- and intermolecular contacts in E protein trimers [37]. The nucleotide sequence of protein E is both sufficiently long and, despite its diversity, adequately conserved for phylogenetic analyses [38]. Furthermore, the gene database contains a vast amount of information regarding numerous E protein records with origins spanning diverse geographic locations. Several mutations in domain III have been identified, which can significantly impact the neurovirulence and neuroinvasiveness of TBEV, Louping-ill virus, and Langat virus [39,40,41,42,43][39][40][41][42][43]. A single amino acid substitution in domains I, II, or III of the E protein transcript has the potential to result in the attenuation of neurovirulence or neuroinvasiveness [40,44,45,46,47][40][44][45][46][47].

2.2.2. Nonstructural Proteins

The NS1 protein, consisting of 351 residues and weighing 46 kDa, is a glycoprotein known for its high conservation. During synthesis, it translocates to the ER. The host signal peptidase cleaves it from the E protein. Within infected cells, the NS1 protein serves as a cofactor in viral RNA replication. It has the ability to form homodimers, and when in the hexameric form (composed of three homodimers), it is released into the serum of patients. Hexameric NS1 proteins form a ring-like structure with a diameter of approximately 10 nm. They are internalized by hepatocytes and transported to late endosomes, where they accumulate and exert immunomodulatory activities [23,48,49,50][23][48][49][50]. The NS2A protein, comprising 229 residues and weighing 22 kDa, is a relatively small hydrophobic protein. It is believed to have a function in binding matrix RNA to the ER membrane within the replication complex [48]. The NS2B protein, consisting of 130 residues and weighing 14 kDa, is a small, membrane-bound protein. It forms a stable complex with the NS3 protein and acts as a cofactor for the serine protease activity of the NS3 protein. On the other hand, the NS3 protein, a large cytoplasmic protein of 621 residues weighing 70 kDa, associates with the membrane through its interaction with the NS2B protein. It plays a multifaceted role in viral replication, serving as a helicase, an RNA triphosphatase, and, when bound to the NS2B protein, a serine protease [51]. The NS2B-3 protease plays a crucial role in mediating most of the cleavages within the nonstructural region of the viral polyprotein, including the cleavage that releases the C protein from the transmembrane signal sequence. Additionally, during helicase activity, it utilizes the energy derived from the hydrolysis of nucleoside triphosphates (NTPs) to unwind the newly formed RNA from the matrix and unravel the secondary structures that mark the beginning of replication. Furthermore, it is involved in modifying the 5′ end of the genome through its RNA triphosphatase activity [51]. The NS4A protein, consisting of 149 residues and weighing 16 kDa, and the NS4B protein, composed of 252 residues and weighing 27 kDa, are small hydrophobic proteins. Their primary role is to anchor the polyprotein, which is synthesized during the translation of the virus genome, into intracellular membranes. This anchoring facilitates the proper functioning of the polymerase complex and ensures the accurate cleavage of the polyprotein [48,51][48][51]. The NS5 protein, comprising 902 residues and weighing 103 kDa, stands as the largest nonstructural protein found in flaviviruses. It holds the distinction of being the most conserved and stable component of the viral genome. Playing a pivotal role, it serves as a central hub for viral RNA replication. The NS5 protein encompasses viral RNA-dependent RNA polymerase activity and exhibits methyltransferase activity, crucial for stabilizing and translating the RNA molecule. Moreover, it actively participates in suppressing the immune response, making it a significant virulence factor [52,53][52][53].

2.3. Multiplication of the Virus

The genome of viruses with positive-polar single-stranded RNA simultaneously enables the transfer of information embedded in RNA from one generation of viruses to another and the formation of proteins in the process of translation. The initial stage of TBEV replication involves the attachment of the virus to the host cell surface. This attachment is facilitated through receptor-mediated binding of virus particles to cells [54,55,56][54][55][56]. The association occurs between the viral envelope E protein and the cellular glycosaminoglycan heparan sulfate, which is abundantly represented on the membranes of various vertebrate and tick cells [32,57,58][32][57][58]. The primary mode of entry for the virus into host cells is through receptor-mediated endocytosis, although entry through micropinocytosis is also possible [25,59,60,61][25][59][60][61]. Initially, the virus is localized within the prelysosomal endocytic vesicle of the host cell. The acidic pH environment within the endosomes triggers conformational changes in the envelope E protein, causing its redistribution. This event ultimately results in the fusion of the viral membrane with the membrane of the endocytic vesicle [62,63][62][63]. Upon entering the host cytoplasm, the nucleocapsid releases the genomic RNA. The process of viral protein synthesis is initiated through RNA translation, followed by replication of the viral genome. Replication of the viral genome involves two steps: amplification of the genomic RNA into a negative-polar RNA copy, which serves as a template, and subsequent transcription of the positive-polar RNA by the RNA-dependent RNA polymerase (RNA replicase). The positive-polar RNA is complementary to the genomic RNA. The genome of TBEV is initially translated at the ER as a single polyprotein. This polyprotein undergoes subsequent cleavage by both viral and host enzymes, leading to the generation of both structural and nonstructural proteins [13]. After translation, the prM and E proteins undergo transport into the ER lumen. The nucleocapsid, composed of several copies of the C protein and one copy of the genomic RNA, forms on the cytoplasmic side of the ER membrane. Subsequently, the nucleocapsid buds from the ER, acquiring a lipid envelope in the process (Figure 2) [64].
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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).
Non-infectious, immature virus particles are produced, their surfaces are covered with trimers of prM and E proteins, and they are easily transmitted through the host’s secretory pathway. Intact prM peptides cover the fusion loops of the E proteins and thus prevent fusion of the virus with intracellular membranes [65]. In addition, sub-viral particles that lack the nucleocapsid are also produced in the ER. Even after maturation, sub-viral particles remain non-infectious [29]. Viral maturation occurs when a host protease cleaves prM in cisternae of the trans-Golgi network [30,65][30][65]. The low pH induces a redistribution of the E protein that generates fusion-competent homodimers in a herringbone-like arrangement and the pr peptides docked onto the fusion loops, a configuration similar to that of the mature virion [65]. Following the cleavage of prM, the dissociation of pr peptides is pH-dependent, indicating that pr is retained on the virion within the acidic environment of the trans-Golgi network. This retention serves to prevent premature membrane fusion [66]. Upon release of the virions from infected cells into the extracellular space with a neutral pH, the pr peptides dissociate from the viral particles. This dissociation leads to the maturation of the virions, making them fusion-competent [65,67,68,69][65][67][68][69]. Mature, infectious viruses that express proteins M and E on their surface are released from the cell by exocytosis (Figure 2) [20,23,24,69,70][20][23][24][69][70].

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