The Relationship between the Structure of the Tick-Borne Encephalitis Virus Strains and Their Pathogenic Properties

Abstract

Tick-borne encephalitis virus (TBEV) is transmitted to vertebrates by taiga or forest ticks through bites, inducing disease of variable severity. The reasons underlying these differences in the severity of the disease are unknown. In order to identify genetic factors affecting the pathogenicity of virus strains, we have sequenced and compared the complete genomes of 34 Far-Eastern subtype (FE) TBEV strains isolated from patients with different disease severity (Primorye, the Russian Far East). We analyzed the complete genomes of 11 human pathogenic strains isolated from the brains of dead patients with the encephalitic form of the disease (Efd), 4 strains from the blood of patients with the febrile form of TBE (Ffd), and 19 strains from patients with the subclinical form of TBE (Sfd). On the phylogenetic tree, pathogenic Efd strains formed two clusters containing the prototype strains, Senzhang and Sofjin, respectively. Sfd strains formed a third separate cluster, including the Oshima strain. The strains that caused the febrile form of the disease did not form a separate cluster. In the viral proteins, we found 198 positions with at least one amino acid residue substitution, of which only 17 amino acid residue substitutions were correlated with the variable pathogenicity of these strains in humans and they authentically differed between the groups. We considered the role of each amino acid substitution and assumed that the deletion of 111 amino acids in the capsid protein in combination with the amino acid substitutions R16K and S45F in the NS3 protease may affect the budding process of viral particles. These changes may be the major reason for the diminished pathogenicity of TBEV strains. We recommend Sfd strains for testing as attenuation vaccine candidates.

Molecular Mechanisms of Interaction Between Human Immune Cells and Far Eastern Tick-Borne Encephalitis Virus Strains

“…This study continued the authors' experimental research of the biological and molecular genetic features of TBEV strains, isolated from people with various forms of disease in the Russian Far East (6,(24)(25)(26)40). This research in animal models, mostly mice, has shown that pathogenic potential (virulence) of the strains isolated from patients with inapparent infection was significantly lower compared to the strains causing severe focal TBE (6,25).…”

“…This research in animal models, mostly mice, has shown that pathogenic potential (virulence) of the strains isolated from patients with inapparent infection was significantly lower compared to the strains causing severe focal TBE (6,25). In cell culture models (PK cells and culture of human peripheral blood mononuclear cells), it has been found that TBEV strains differ in their replicative activity: nonpathogenic strains have lower rates of penetration and replication of viral particles in cells than pathogenic strains (20,26).…”

“…The P-183 strain, isolated in 1991 from the blood leukocytes of a person with an inapparent form of TBE, is nonpathogenic in humans (Gene Bank Whole Genome Sequence Number: JQ825153). Isolation of these strains and the study of their molecular genetic characteristics and biological properties was performed as previously described (6,25,26). In this study, the brains of infected suckling mice (Dal strain: 9 passage; P-183 strain: 5 passage) stored at -80°C were taken.…”

“…In the endemic areas, where TBEV strains of the Far Eastern subtype circulate, severe forms of disease with high mortality rates that can exceed 20% (23) are detected more often than in the regions dominated by virus strains of Siberian and European subtypes. Besides, each TBEV subtype includes genetically different lines or clusters that indicate heterogeneity of a virus population that can cause various forms of disease (6,13,25). A number of authors, who have described clinical polymorphism of TBE, link it to genotypic and phenotypic variability of the TBEV population (38,65).…”

Correlation of Severity of Human Tick-Borne Encephalitis Virus Disease and Pathogenicity in Mice

“…The mice showed a strong cytokine response in periphery, low and delayed neuroinvasiveness, and low neurovirulence that, when translated into humans, might explain the lack of neurologic symptoms. Because genetic changes in TBEV could affect pathogenicity ( 12 , 13 ), future molecular studies are needed to determine the low pathogenicity of and enhanced immune response against low-virulence strain HB171/11.…”