Emerging flaviviruses are causative agents of severe and life-threatening diseases, against which no approved therapies are available. Among the nucleoside analogues, which represent a promising ...group of potentially therapeutic compounds, fluorine-substituted nucleosides are characterized by unique structural and functional properties. Despite having first been synthesized almost 5 decades ago, they still offer new therapeutic opportunities as inhibitors of essential viral or cellular enzymes active in nucleic acid replication/transcription or nucleoside/nucleotide metabolism. Here, we report evaluation of the antiflaviviral activity of 28 nucleoside analogues, each modified with a fluoro substituent at different positions of the ribose ring and/or heterocyclic nucleobase. Our antiviral screening revealed that 3'-deoxy-3'-fluoroadenosine exerted a low-micromolar antiviral effect against tick-borne encephalitis virus (TBEV), Zika virus, and West Nile virus (WNV) (EC
values from 1.1 ± 0.1 μM to 4.7 ± 1.5 μM), which was manifested in host cell lines of neural and extraneural origin. The compound did not display any measurable cytotoxicity up to concentrations of 25 μM but had an observable cytostatic effect, resulting in suppression of cell proliferation at concentrations of >12.5 μM. Novel approaches based on quantitative phase imaging using holographic microscopy were developed for advanced characterization of antiviral and cytotoxic profiles of 3'-deoxy-3'-fluoroadenosine
In addition to its antiviral activity in cell cultures, 3'-deoxy-3'-fluoroadenosine was active
in mouse models of TBEV and WNV infection. Our results demonstrate that fluoro-modified nucleosides represent a group of bioactive molecules with excellent potential to serve as prospective broad-spectrum antivirals in antiviral research and drug development.
Tick-borne encephalitis virus (TBEV) is transmitted mainly by tick bites, but humans can acquire infection through consuming unpasteurized milk from infected animals. Interhuman transmission of TBEV ...by breast milk has not been confirmed or ruled out. We report a case of probable transmission of TBEV from an unvaccinated mother to an infant through breast-feeding.
Tick‐borne encephalitis virus (TBEV) is an important causative agent that causes neurological infections in humans and animals. In recent years, only few epidemiological surveys on TBEV have been ...conducted in China. The purpose of this study was to determine the prevalence and subtype of TBEV in ticks in northeastern (NE) China. A total of 3799 questing ticks were collected in NE China between April 2015 and June 2016. Ticks were pooled and tested for TBEV RNA using semi‐nested reverse transcriptase‐polymerase chain reaction. Positive pools were used to isolate the virus and amplify complete sequences, followed by sequence identity and phylogenetic analysis. TBEV RNA was detected in Ixodes persulcatus ticks at a total prevalence of 2.9% (6/143; 95% confidence interval: 1.2%–5.9%). Three TBEV strains were isolated (JL‐T75, HLB‐T74, and DXAL‐T83) and showed 93.9%–99.1% nucleotide identities and 97.1%–99.5% amino acid identities in Far Eastern (FE) TBEV subtypes, and 82.9%–87.6% nucleotide identities and 92.9%–96.4% amino acid identities in other subtypes. For polyprotein, the JL‐T75, HLB‐T74, and DXAL‐T83 strains showed 29, 50, and 55 amino acid residues, respectively, different from those in the TBEV vaccine (Senzhang) strain in China. Phylogenetic analysis revealed that these viruses were clustered in the FE‐TBEV branch but formed distinct clades depending on the natural foci. The results of this study suggest that the FE‐TBEV subtype is still endemic in I. persulcatus ticks in NE China, and the viruses in different natural foci in NE China are more likely to have genetic differences.
Highlights
FE‐TBEV subtype is still endemic in I.
persulcatus ticks in northeastern (NE) China with a total prevalence of 2.9%.
TBEV in different natural foci in NE China are more likely to have genetic differences.
Genetic differences may not affect the immunological protection of vaccination with the Senzhang strain in NE China.
Arthropod‐borne flaviviruses include a number of medically relevant human pathogens such as the mosquito‐borne dengue (DEN), Zika, and yellow fever (YF) viruses as well as tick‐borne encephalitis ...virus (TBEV). All flaviviruses are antigenically related and anamnestic responses due to prior immunity can modulate antibody specificities in subsequent infections or vaccinations. In our study, we analyzed the induction of broadly flavivirus cross‐reactive antibodies in tick‐borne encephalitis (TBE) and DEN patients without or with prior flavivirus exposure through TBE and/or YF vaccination, and determined the contribution of these antibodies to TBE and dengue virus (DENV) neutralization. In addition, we investigated the formation of cross‐reactive antibodies in TBE‐vaccination breakthroughs (VBTs). A TBEV infection without prior YF or TBE vaccination induced predominantly type‐specific antibodies. In contrast, high levels of broadly cross‐reactive antibodies were found in samples from TBE patients prevaccinated against YF as well as in DEN patients prevaccinated against TBE and/or YF. While these cross‐reactive antibodies did not neutralize TBEV, they were effective in neutralizing DENV. This discrepancy points to structural differences between the two viruses and indicates that broadly cross‐reactive epitopes are less accessible in TBEV than in DENV. In TBE VBT infections, type‐specific antibodies dominated the antibody response, thus revealing no difference from that of unvaccinated TBE patients. Our results emphasize significant differences in the structural properties of different flaviviruses that have an impact on the induction of broadly cross‐reactive antibodies and their functional activities in virus neutralization.
Background and purpose
Tick‐borne encephalitis (TBE) is a common viral disease in central Europe and Asia. Severe or even lethal neurological symptoms may ensue. With limited therapeutic options, ...active vaccination against the TBE virus (TBEV) is strongly recommended in endemic areas. A systematic analysis of the clinical picture and cerebral imaging findings associated with TBE was conducted with particular focus on patients who acquired TBE despite previous vaccination.
Methods
A cohort of 52 patients with serologically proven TBE treated at our centre in a 10‐year period who received at least one cerebral magnetic resonance imaging (MRI) was retrospectively described. Extension of MRI changes was systematically assessed by an experienced neuroradiologist. Standard statistical procedures were performed.
Results
Fifty‐two patients with a definite serological diagnosis of TBE were included. The most common presentation was encephalitis (67%). MRI showed TBE‐associated parenchymal lesions in 33% of all patients. Sites of predilection included the periaqueductal grey, the thalamus and the brainstem. Ten patients had received at least one prior active or passive TBEV immunization. All of these had a maximal Rankin Scale score of at least 4. The median number of affected anatomical regions on MRI was significantly higher than in the non‐vaccinated cohort.
Conclusions
To our knowledge, this is the first study systematically describing the peculiarities of MRI in patients vaccinated against TBE. In addition to a severe clinical course, they exhibit more extensive MRI lesions than a non‐vaccinated cohort. Possible reasons for these findings include incomplete seroconversion, more virulent TBEV strains or antibody‐dependent enhancement.
The tick‐borne encephalitis virus (TBEV) serocomplex includes several medically important flavivirus members endemic to Europe, Asia, and North America, which can induce severe neuroinvasive or ...viscerotropic diseases with unclear mechanisms of pathogenesis. Langat virus (LGTV) shares a high sequence identity with TBEV but exhibits lower pathogenic potential in humans and serves as a model for virus‐host interactions. In this study, we demonstrated that LGTV infection inhibits the activation of gp130/JAK/STAT (Janus kinases (JAK) and signal transducer and activator of transcription (STAT)) signaling, which plays a pivotal role in numerous biological processes. Our data show that the LGTV‐infected cells had significantly lower phosphorylated STAT3 (pSTAT3) protein upon oncostatin M (OSM) stimulation than the mock‐infected control. LGTV infection blocked the nuclear translocation of STAT3 without a significant effect on total STAT3 protein level. LGTV inhibited JAK1 activation and reduced gp130 protein expression in infected cells, with the viral NS5 protein mediating this effect. TBEV infection also reduces gp130 level. On the other hand, pretreatment of Vero cells with OSM significantly reduces LGTV replication, and STAT1/STAT2 knockdown had little effect on OSM‐mediated antiviral effect, which suggests it is independent of STAT1/STAT2 and, instead, it is potentially mediated by STAT3 signlaing. These findings shed light on the LGTV and TBEV‐cell interactions, offering insights for the future development of antiviral therapeutics and improved vaccines.
We report the presence of tick-borne encephalitis virus (TBEV) in the Netherlands. Serologic screening of roe deer found TBEV-neutralizing antibodies with a seroprevalence of 2%, and TBEV RNA was ...detected in 2 ticks from the same location. Enhanced surveillance and awareness among medical professionals has led to the identification of autochthonous cases.
The study of virus structures by X‐ray free‐electron lasers (XFELs) has attracted increased attention in recent decades. Such experiments are based on the collection of 2D diffraction patterns ...measured at the detector following the application of femtosecond X‐ray pulses to biological samples. To prepare an experiment at the European XFEL, the diffraction data for the tick‐borne encephalitis virus (TBEV) was simulated with different parameters and the optimal values were identified. Following the necessary steps of a well established data‐processing pipeline, the structure of TBEV was obtained. In the structure determination presented, a priori knowledge of the simulated virus orientations was used. The efficiency of the proposed pipeline was demonstrated.
In this work, a single‐particle imaging experiment of tick‐borne encephalitis virus at the European XFEL was simulated. These simulations allow the optimal parameters of the experimental setup to be obtained for use in future experiments.
Tick-borne encephalitis virus (TBEV) belongs to the family Flaviviridae. Flaviviruses are 50 nm viruses having a membrane envelope with an RNA genome. The vector of TBEV is the common tick (Ixodes ...ricinus) prevalent mainly in Europe. Tick-borne encephalitis is endemic in 27 countries in Europe. According to the National Institute of Hygiene, there are several hundred cases per year in Poland. Diagnosis of TBEV may be based on serological tests, molecular tests, cerebrospinal fluid examination. Prevention of tick-borne encephalitis is based on several aspects and the most important are the non-compulsory vaccinations. TBEV is a disease characterised by the risk of many complications, which can be irreversible. Fortunately, thanks to developments in vaccinology, vaccinations are available to prevent infection or reduce the severity of the disease.
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