scholarly journals Molecular Basis of a Protective/Neutralizing Monoclonal Antibody Targeting Envelope Proteins of both Tick-Borne Encephalitis Virus and Louping Ill Virus

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Xu Yang ◽  
Jianxun Qi ◽  
Ruchao Peng ◽  
Lianpan Dai ◽  
Ernest A. Gould ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Encephalitis Virus ◽  
Infection Rates ◽  
E Proteins ◽  
E Protein ◽  
Tick Borne Encephalitis ◽  
The Family ◽  
Lateral Ridge ◽  
Louping Ill ◽  
Tick Borne Encephalitis Virus

ABSTRACT Tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) are members of the tick-borne flaviviruses (TBFVs) in the family Flaviviridae which cause encephalomeningitis and encephalitis in humans and other animals. Although vaccines against TBEV and LIV are available, infection rates are rising due to the low vaccination coverage. To date, no specific therapeutics have been licensed. Several neutralizing monoclonal antibodies (MAbs) show promising effectiveness in the control of TBFVs, but the underlying molecular mechanisms are yet to be characterized. Here, we determined the crystal structures of the LIV envelope (E) protein and report the comparative structural analysis of a TBFV broadly neutralizing murine MAb (MAb 4.2) in complex with either the LIV or TBEV E protein. The structures reveal that MAb 4.2 binds to the lateral ridge of domain III of the E protein (EDIII) of LIV or TBEV, an epitope also reported for other potently neutralizing MAbs against mosquito-borne flaviviruses (MBFVs), but adopts a unique binding orientation. Further structural analysis suggested that MAb 4.2 may neutralize flavivirus infection by preventing the structural rearrangement required for membrane fusion during virus entry. These findings extend our understanding of the vulnerability of TBFVs and other flaviviruses (including MBFVs) and provide an avenue for antibody-based TBFV antiviral development. IMPORTANCE Understanding the mechanism of antibody neutralization/protection against a virus is crucial for antiviral countermeasure development. Tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) are tick-borne flaviviruses (TBFVs) in the family Flaviviridae. They cause encephalomeningitis and encephalitis in humans and other animals. Although vaccines for both viruses are available, infection rates are rising due to low vaccination coverage. In this study, we solved the crystal structures of the LIV envelope protein (E) and a broadly neutralizing/protective TBFV MAb, MAb 4.2, in complex with E from either TBEV or LIV. Key structural features shared by TBFV E proteins were analyzed. The structures of E-antibody complexes showed that MAb 4.2 targets the lateral ridge of both the TBEV and LIV E proteins, a vulnerable site in flaviviruses for other potent neutralizing MAbs. Thus, this site represents a promising target for TBFV antiviral development. Further, these structures provide important information for understanding TBFV antigenicity.

scholarly journals The serological response and long-lasting resistance against infection with louping-ill virus in sheep immunized with a highly attenuated tick-borne encephalitis virus

1969 ◽  
Vol 67 (4) ◽  
pp. 731-738 ◽  
Author(s):  
V. Mayer ◽  
D. Blaškovič ◽  
E. Ernek ◽  
H. Libíková
Keyword(s):  
Neutralizing Antibodies ◽  
Encephalitis Virus ◽  
Serological Response ◽  
Immune Control ◽  
Summer Period ◽  
Tick Borne Encephalitis ◽  
Louping Ill ◽  
Tick Borne Encephalitis Virus

SUMMARYThe vaccination of sheep with one dose of the monkey-and mouse-attenuated tick-borne encephalitis virus (the Hy-HK 28 ‘2’ clone) causes seroconversion from negative into positive in 85% of animals. In sheep with pre-existing virus-neutralizing antibodies and increas of their titres was observed in 81%. The antibodies persisted for at least 12 months after the vaccination and during the summer period of grazing the number of serologically positive animals even increased.The vaccinated animals, in contrast to the non-immune control sheep, developed no viraemia after challenge with the virulent louping-ill virus, performed 11 months after immunization.

scholarly journals Tick-Borne Encephalitis Virus: A Quest for Better Vaccines against a Virus on the Rise

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 451 ◽  
Author(s):  
Mareike Kubinski ◽  
Jana Beicht ◽  
Thomas Gerlach ◽  
Asisa Volz ◽  
Gerd Sutter ◽  
...  
Keyword(s):  
Antiviral Treatment ◽  
Encephalitis Virus ◽  
Protective Measure ◽  
Humoral And Cellular Immunity ◽  
Tick Borne Encephalitis ◽  
The Family ◽  
The Central Nervous System ◽  
Tick Borne Encephalitis Virus ◽  
Protection Against Infection ◽  
Vaccine Failures

Tick-borne encephalitis virus (TBEV), a member of the family Flaviviridae, is one of the most important tick-transmitted viruses in Europe and Asia. Being a neurotropic virus, TBEV causes infection of the central nervous system, leading to various (permanent) neurological disorders summarized as tick-borne encephalitis (TBE). The incidence of TBE cases has increased due to the expansion of TBEV and its vectors. Since antiviral treatment is lacking, vaccination against TBEV is the most important protective measure. However, vaccination coverage is relatively low and immunogenicity of the currently available vaccines is limited, which may account for the vaccine failures that are observed. Understanding the TBEV-specific correlates of protection is of pivotal importance for developing novel and improved TBEV vaccines. For affording robust protection against infection and development of TBE, vaccines should induce both humoral and cellular immunity. In this review, the adaptive immunity induced upon TBEV infection and vaccination as well as novel approaches to produce improved TBEV vaccines are discussed.

Tick-borne encephalitides

2011 ◽  
Author(s):  
Patricia A. Nuttall
Keyword(s):  
North America ◽  
Tick Species ◽  
Encephalitis Virus ◽  
Virus Family ◽  
Wild Mammals ◽  
Tick Borne Encephalitis ◽  
Powassan Virus ◽  
Louping Ill ◽  
Tick Borne Encephalitis Virus ◽  
Far Eastern

Tick-borne encephalitides are caused by three different viruses transmitted by ticks and belonging to the Flaviviridae virus family: tick-borne encephalitis virus (Far Eastern, Siberian, and European subtypes), louping ill virus, and Powassan virus (including deer tick virus). These viruses cause encephalitis affecting humans in Eurasia and North America. In nature, they are maintained in transmission cycles involving Ixodes tick species and small or medium-sized wild mammals. The tick-borne flavivirus group is one of the most intensely studied groups of tick-borne pathogens.

scholarly journals Spectrum of antiviral activity of 4-aminopyrimidine N-oxides against a broad panel of tick-borne encephalitis virus strains

2020 ◽  
Vol 28 ◽  
pp. 204020662094346
Author(s):  
Evgenia V Dueva ◽  
Ksenia K Tuchynskaya ◽  
Liubov I Kozlovskaya ◽  
Dmitry I Osolodkin ◽  
Kseniya N Sedenkova ◽  
...  
Keyword(s):  
Encephalitis Virus ◽  
Northern Eurasia ◽  
Virus Particles ◽  
E Protein ◽  
Tick Borne Encephalitis ◽  
Tbev Strain ◽  
Amino Phenol ◽  
Tick Borne Encephalitis Virus ◽  
Immature Virus

Tick-borne encephalitis is an important human arbovirus neuroinfection spread across the Northern Eurasia. Inhibitors of tick-borne encephalitis virus (TBEV) strain Absettarov, presumably targeting E protein n-octyl-β-d-glucoside (β-OG) pocket, were reported earlier. In this work, these inhibitors were tested in vitro against seven strains representing three main TBEV subtypes. The most potent compound, 2-[(2-methyl-1-oxido-5,6,7,8-tetrahydroquinazolin-4-yl)amino]-phenol, showed EC50 values lower than 22 µM against all the tested strains. Nevertheless, EC50 values for virus samples of certain strains demonstrated a substantial variation, which appeared to be consistent with the presence of E protein not only in infectious virions, but also in non-infectious and immature virus particles, protein aggregates, and membrane complexes.

scholarly journals Flavivirus-induced antibody cross-reactivity

2011 ◽  
Vol 92 (12) ◽  
pp. 2821-2829 ◽  
Author(s):  
Karen L. Mansfield ◽  
Daniel L. Horton ◽  
Nicholas Johnson ◽  
Li Li ◽  
Alan D. T. Barrett ◽  
...  
Keyword(s):  
Yellow Fever Virus ◽  
Cross Reactivity ◽  
Encephalitis Virus ◽  
Antigenic Relationship ◽  
Tick Borne Encephalitis ◽  
History Of ◽  
Louping Ill ◽  
Tick Borne Encephalitis Virus ◽  
Antigenic Cartography ◽  
The Individual

Dengue viruses (DENV) cause countless human deaths each year, whilst West Nile virus (WNV) has re-emerged as an important human pathogen. There are currently no WNV or DENV vaccines licensed for human use, yet vaccines exist against other flaviviruses. To investigate flavivirus cross-reactivity, sera from a human cohort with a history of vaccination against tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV) and yellow fever virus (YFV) were tested for antibodies by plaque reduction neutralization test. Neutralization of louping ill virus (LIV) occurred, but no significant neutralization of Murray Valley encephalitis virus was observed. Sera from some individuals vaccinated against TBEV and JEV neutralized WNV, which was enhanced by YFV vaccination in some recipients. Similarly, some individuals neutralized DENV-2, but this was not significantly influenced by YFV vaccination. Antigenic cartography techniques were used to generate a geometric illustration of the neutralization titres of selected sera against WNV, TBEV, JEV, LIV, YFV and DENV-2. This demonstrated the individual variation in antibody responses. Most sera had detectable titres against LIV and some had titres against WNV and DENV-2. Generally, LIV titres were similar to titres against TBEV, confirming the close antigenic relationship between TBEV and LIV. JEV was also antigenically closer to TBEV than WNV, using these sera. The use of sera from individuals vaccinated against multiple pathogens is unique relative to previous applications of antigenic cartography techniques. It is evident from these data that notable differences exist between amino acid sequence identity and mapped antigenic relationships within the family Flaviviridae.

Susceptibility of Tick-Borne Encephalitis Virus to Inactivation by Heat, Acidic pH, Chemical, or UV Treatment

2020 ◽  
Author(s):  
Laura Wiesner ◽  
Carla Schmutte ◽  
Imke Steffen
Keyword(s):  
Occupational Exposure ◽  
Sample Size ◽  
Rna Virus ◽  
Encephalitis Virus ◽  
Acidic Ph ◽  
Uv Treatment ◽  
Tick Borne Encephalitis ◽  
The Family ◽  
Positive Sense ◽  
Tick Borne Encephalitis Virus

Abstract Tick-borne encephalitis virus (TBEV) is a single-stranded, positive-sense RNA virus in the family Flaviviridae that is endemic in parts of Europe and Asia and can cause meningitis or encephalitis. Due to the disease severity, TBEV requires handling under heightened biosafety measures. The establishment and validation of inactivation procedures is a prerequisite for downstream analyses and management of occupational exposure. Therefore, different procedures for TBEV inactivation were tested. Our results suggest that TBEV is susceptible to inactivation by heat, acidic pH, different concentrations of alcohol, formaldehyde, or detergents, and exposure to UV irradiation, which may depend on sample size and composition.

scholarly journals Impact of Quaternary Organization on the Antigenic Structure of the Tick-Borne Encephalitis Virus Envelope Glycoprotein E

2009 ◽  
Vol 83 (17) ◽  
pp. 8482-8491 ◽  
Author(s):  
Stefan Kiermayr ◽  
Karin Stiasny ◽  
Franz X. Heinz
Keyword(s):  
Neutralizing Antibodies ◽  
Encephalitis Virus ◽  
Antigenic Structure ◽  
Icosahedral Symmetry ◽  
Virus Envelope ◽  
E Protein ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus ◽  
Virion Surface ◽  
Subviral Particles

ABSTRACT The envelope protein E of flaviviruses mediates both receptor-binding and membrane fusion. At the virion surface, 180 copies of E are tightly packed and organized in a herringbone-like icosahedral structure, whereas in noninfectious subviral particles, 60 copies are arranged in a T=1 icosahedral symmetry. In both cases, the basic building block is an E dimer which exposes the binding sites for neutralizing antibodies at its surface. It was the objective of our study to assess the dependence of the antigenic structure of E on its quaternary arrangement, i.e., as part of virions, recombinant subviral particles, or soluble dimers. For this purpose, we used a panel of 11 E protein-specific neutralizing monoclonal antibodies, mapped to distinct epitopes in each of the three E protein domains, and studied their reactivity with the different soluble and particulate forms of tick-borne encephalitis virus E protein under nondenaturing immunoassay conditions. Significant differences in the reactivities with these forms were observed that could be related to (i) limited access of certain epitopes at the virion surface; (ii) limited occupancy of epitopes in virions due to steric hindrance between antibodies; (iii) differences in the avidity to soluble forms compared to the virion, presumably related to the flexibility of E at its domain junctions; and (iv) modulations of the external E protein surface through interactions with its stem-anchor structure. We have thus identified several important factors that influence the antigenicity of the flavivirus E protein and have an impact on the interaction with neutralizing antibodies.

scholarly journals The envelope protein of tick-borne encephalitis virus influences neuron entry, pathogenicity, and vaccine protection

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Richard Lindqvist ◽  
Ebba Rosendal ◽  
Elvira Weber ◽  
Naveed Asghar ◽  
Sarah Schreier ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Encephalitis Virus ◽  
Chimeric Virus ◽  
E Protein ◽  
Tick Borne Encephalitis ◽  
Neutralizing Capacity ◽  
Tbev Strain ◽  
Primary Mouse ◽  
Tick Borne Encephalitis Virus

Abstract Background Tick-borne encephalitis virus (TBEV) is considered to be the medically most important arthropod-borne virus in Europe. The symptoms of an infection range from subclinical to mild flu-like disease to lethal encephalitis. The exact determinants of disease severity are not known; however, the virulence of the strain as well as the immune status of the host are thought to be important factors for the outcome of the infection. Here we investigated virulence determinants in TBEV infection. Method Mice were infected with different TBEV strains, and high virulent and low virulent TBEV strains were chosen. Sequence alignment identified differences that were cloned to generate chimera virus. The infection rate of the parental and chimeric virus were evaluated in primary mouse neurons, astrocytes, mouse embryonic fibroblasts, and in vivo. Neutralizing capacity of serum from individuals vaccinated with the FSME-IMMUN® and Encepur® or combined were evaluated. Results We identified a highly pathogenic and neurovirulent TBEV strain, 93/783. Using sequence analysis, we identified the envelope (E) protein of 93/783 as a potential virulence determinant and cloned it into the less pathogenic TBEV strain Torö. We found that the chimeric virus specifically infected primary neurons more efficiently compared to wild-type (WT) Torö and this correlated with enhanced pathogenicity and higher levels of viral RNA in vivo. The E protein is also the major target of neutralizing antibodies; thus, genetic variation in the E protein could influence the efficiency of the two available vaccines, FSME-IMMUN® and Encepur®. As TBEV vaccine breakthroughs have occurred in Europe, we chose to compare neutralizing capacity from individuals vaccinated with the two different vaccines or a combination of them. Our data suggest that the different vaccines do not perform equally well against the two Swedish strains. Conclusions Our findings show that two amino acid substitutions of the E protein found in 93/783, A83T, and A463S enhanced Torö infection of neurons as well as pathogenesis and viral replication in vivo; furthermore, we found that genetic divergence from the vaccine strain resulted in lower neutralizing antibody titers in vaccinated individuals.

scholarly journals Immunogenicity and Protective Activity of a Chimeric Protein Based on the Domain III of the Tick-Borne Encephalitis Virus E Protein and the OmpF Porin of Yersinia pseudotuberculosis Incorporated into the TI-Complex

2018 ◽  
Vol 19 (10) ◽  
pp. 2988
Author(s):  
Nina Sanina ◽  
Natalia Chopenko ◽  
Andrey Mazeika ◽  
Ludmila Davydova ◽  
Galina Leonova ◽  
...  
Keyword(s):  
Yersinia Pseudotuberculosis ◽  
Chimeric Protein ◽  
Encephalitis Virus ◽  
Protective Activity ◽  
Ompf Porin ◽  
E Protein ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus ◽  
Domain Iii ◽  
Ti Complexes

Tick-borne encephalitis (TBE) is a widespread, dangerous infection. Unfortunately, all attempts to create safe anti-TBE subunit vaccines are still unsuccessful due to their low immunogenicity. The goal of the present work was to investigate the immunogenicity of a recombinant chimeric protein created by the fusion of the EIII protein, comprising domain III and a stem region of the tick-borne encephalitis virus (TBEV) E protein, and the OmpF porin of Yersinia pseudotuberculosis (OmpF-EIII). Adjuvanted antigen delivery systems, the tubular immunostimulating complexes (TI-complexes) based on the monogalactosyldiacylglycerol from different marine macrophytes, were used to enhance the immunogenicity of OmpF-EIII. Also, the chimeric protein incorporated into the most effective TI-complex was used to study its protective activity. The content of anti-OmpF-EIII antibodies was estimated in mice blood serum by enzyme-linked immunosorbent assay (ELISA). To study protective activity, previously immunized mice were infected with TBEV strain Dal’negorsk (GenBank ID: FJ402886). The animal survival was monitored daily for 21 days. OmpF-EIII incorporated into the TI-complexes induced about a 30–60- and 5–10-fold increase in the production of anti-OmpF-EIII and anti-EIII antibodies, respectively, in comparison with the effect of an individual OmpF-EIII. The most effective vaccine construction provided 60% protection. Despite the dramatic effect on the specific antibody titer, the studied TI-complex did not provide a statistically significant increase in the protection of OmpF-EIII protein. However, our results provide the basis of the future search for approaches to design and optimize the anti-TBEV vaccine based on the OmpF-EIII protein.

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