Limnological Institute, Siberian Branch, Russian Academy of Sciences, Irkutsk, Russia.
Research Institute of Epidemiology and Microbiology, Siberian Branch, Russian Academy of Medical Sciences, Vladivostok, Russia.
PLoS One. 2014 Apr 16;9(4):e94946. doi: 10.1371/journal.pone.0094946. eCollection 2014.
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.
蜱传脑炎病毒（TBEV）通过蜱的叮咬传播给脊椎动物，引起不同严重程度的疾病。导致这些疾病严重程度差异的原因尚不清楚。为了确定影响病毒株致病性的遗传因素，我们对 34 株来自不同疾病严重程度（俄罗斯远东地区的Primorye）患者的远东型（FE）TBEV 分离株的完整基因组进行了测序和比较。我们分析了 11 株从患有脑炎型疾病（Efd）的死亡患者的脑组织中分离出的人类致病性毒株、4 株从患有发热型 TBE（Ffd）的患者血液中分离出的毒株和 19 株从患有亚临床型 TBE（Sfd）的患者中分离出的毒株的完整基因组。在系统进化树上，致病性 Efd 株形成了两个包含原型株 Senzhang 和 Sofjin 的聚类。Sfd 株形成了第三个独立的聚类，包括大岛株。引起发热型疾病的菌株没有形成单独的聚类。在病毒蛋白中，我们发现了 198 个位置至少有一个氨基酸残基取代，其中只有 17 个氨基酸残基取代与这些株系在人类中的可变致病性相关，并且它们在各组之间确实存在差异。我们考虑了每个氨基酸取代的作用，并假设衣壳蛋白中 111 个氨基酸的缺失与 NS3 蛋白酶中的氨基酸取代 R16K 和 S45F 相结合可能会影响病毒颗粒的出芽过程。这些变化可能是 TBEV 株系致病性降低的主要原因。我们建议使用 Sfd 株系作为减毒疫苗候选株进行测试。
