NS2B/NS3 protease: allosteric effect of mutations associated with the pathogenicity of tick-borne encephalitis virus

Potapova, Ulyana; Feranchuk, Sergey; Potapov, V. V.; Kulakova, Nina V.; Кондратов, И. Г.; Леонова, Г Н; Беликов, С. И.

doi:10.1080/07391102.2012.689697

Cited by 16 publications

(10 citation statements)

References 49 publications

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“…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).…”

Section: Discussionmentioning

confidence: 88%

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

2015

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Although studies have established that immune mechanisms are important in controlling tick-borne encephalitis virus (TBEV) infection, the interactions of different TBEV strains with cells of innate and adaptive immunity are not well understood. In this study, the ability of two Far Eastern subtype TBEV strains (Dal'negorsk and Primorye-183) with various degrees of pathogenicity for humans to modulate the expression of membrane molecules differently on human immune cells were investigated using a whole-blood flow cytometry-based assay. The whole-blood samples (from 10 healthy donors) were infected with TBEV strains and analyzed for the virus binding to the blood cells, as well as expression of adhesion (CD11b and ICAM-1) and activation (CD69, CD25, CD95) molecules on the surfaces of monocytes, granulocytes, natural killer (NK) cells, and T-lymphocytes (CD4+, CD8+) at selected times (3, 6, and 24 h post-infection). It was found that the highly pathogenic Dal'negorsk strain penetrated rapidly and was actively replicated in the blood cells, inducing downregulation of CD11b, ICAM-1, and CD69 on monocytes and a significant decrease of NK cells expressing CD69, CD25, CD95, and CD8 T-lymphocytes expressing CD69 compared with the mock-infected cells. The nonpathogenic Primorye-183 strain penetrated slowly and was replicated in the blood cells, but caused a significant increase in the adhesion and activation of molecule expression to trigger innate defense mechanisms and enable the rapid elimination of the virus from the organism. Thus, TBEV-induced activation or suppression of adhesion and activation receptors expression form an essential part of fundamental virus properties, that is, virulence and pathogenicity.

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Section: Discussionmentioning

confidence: 88%

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

2015

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“…Sfd strains possessed two key substitutions, R16K and S45F in the NS3 protein, located in the protease domain, but outside the active center. Molecular dynamic simulations indicated that changes in the conformation of the NS3/NS2B complex in Sfd strains might hinder the formation of the polyprotein/protease complex and reduce the hydrolysis rate of the polyprotein [81] (Figure 4). The biological properties of the Skotovo-94 strain confirm these calculations.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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“…The NS3 protease of DENV plays a crucial role in virus replication by cleaving the full-length viral polyprotein into mature functional proteins (22). A previous study showed that amino acid substitutions in the NS3 protein of the tick-borne encephalitis virus caused conformational changes in the active protease domain of the NS2B-NS3 protease complex that influenced enzyme function and virulence (23).…”

Section: Discussionmentioning

confidence: 99%

Adaptation and Attenuation of Duck Tembusu Virus Strain Du/CH/LSD/110128 following Serial Passage in Chicken Embryos

Sun

Zhang

et al. 2014

Clin. Vaccine Immunol.

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Duck Tembusu virus (DTMUV) is a newly emerging pathogenic flavivirus that has caused massive economic losses to the duck industry in China. In the current study, a virulent strain of DTMUV, designated Du/CH/LSD/110128, was isolated from the livers of diseased ducks and attenuated by serial passage in embryonated chicken eggs. The virus was partially attenuated after 50 and 70 passages and was fully attenuated after 90 passages, based on mortality and morbidity rates and viral loads in inoculated ducklings. Fourteen amino acid substitutions were observed in the capsid, prM, envelope, NS1, NS3, NS4A, NS4B, and NS5 proteins of the fully attenuated strain of Du/CH/LSD/110128, which might be responsible for the observed changes in replication and pathogenicity. A 72-nucleotide deletion was also observed in the 3= untranslated region of the virus after 30 passages. The fully attenuated virus retained the immunogenicity of the parental strain, providing effective protection to challenge with virulent Du/CH/LSD/110128, and may represent a suitable candidate as a vaccine strain against DTMUV infection in ducks. Our results also lay the foundation for future studies on the replication and pathogenic mechanisms of DTMUV.

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NS2B/NS3 protease: allosteric effect of mutations associated with the pathogenicity of tick-borne encephalitis virus

Cited by 16 publications

References 49 publications

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

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

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

Adaptation and Attenuation of Duck Tembusu Virus Strain Du/CH/LSD/110128 following Serial Passage in Chicken Embryos

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