Tick-borne encephalitis (TBE) is an illness caused by tick-borne encephalitis virus (TBEV) infection which is often limited to a febrile illness, but may lead to very aggressive downstream ...neurological manifestations. The disease is prevalent in forested areas of Europe and northeastern Asia, and is typically caused by infection involving one of three TBEV subtypes, namely the European (TBEV-Eu), the Siberian (TBEV-Sib), or the Far Eastern (TBEV-FE) subtypes. In addition to the three main TBEV subtypes, two other subtypes; i.e., the Baikalian (TBEV-Bkl) and the Himalayan subtype (TBEV-Him), have been described recently. In Europe, TBEV-Eu infection usually results in only mild TBE associated with a mortality rate of <2%. TBEV-Sib infection also results in a generally mild TBE associated with a non-paralytic febrile form of encephalitis, although there is a tendency towards persistent TBE caused by chronic viral infection. TBE-FE infection is considered to induce the most severe forms of TBE. Importantly though, viral subtype is not the sole determinant of TBE severity; both mild and severe cases of TBE are in fact associated with infection by any of the subtypes. In keeping with this observation, the overall TBE mortality rate in Russia is ∼2%, in spite of the fact that TBEV-Sib and TBEV-FE subtypes appear to be inducers of more severe TBE than TBEV-Eu. On the other hand, TBEV-Sib and TBEV-FE subtype infections in Russia are associated with essentially unique forms of TBE rarely seen elsewhere if at all, such as the hemorrhagic and chronic (progressive) forms of the disease. For post-exposure prophylaxis and TBE treatment in Russia and Kazakhstan, a specific anti-TBEV immunoglobulin is currently used with well-documented efficacy, but the use of specific TBEV immunoglobulins has been discontinued in Europe due to concerns regarding antibody-enhanced disease in naïve individuals. Therefore, new treatments are essential. This review summarizes available data on the pathogenesis and clinical features of TBE, plus different vaccine preparations available in Europe and Russia. In addition, new treatment possibilities, including small molecule drugs and experimental immunotherapies are reviewed. The authors caution that their descriptions of approved or experimental therapies should not be considered to be recommendations for patient care.
•Tick-borne encephalitis (TBE) is an acute febrile viral illness with neurological manifestations.•No specific antivirals are approved for TBE therapy.•A number of nucleoside or non-nucleoside antivirals exhibit anti-TBE virus (TBEV) activity in vitro and in vivo.•Specific anti-TBEV immunoglobulin is used for post-exposure prophylaxis and TBE treatment in Russia but not in Europe.•TBE is preventable by effective vaccines but vaccination coverage remains low in many endemic countries.
During February 2018-January 2019, we conducted large-scale surveillance for the presence and prevalence of tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) in sentinel animals and ...ticks in the United Kingdom. Serum was collected from 1,309 deer culled across England and Scotland. Overall, 4% of samples were ELISA-positive for the TBEV serocomplex. A focus in the Thetford Forest area had the highest proportion (47.7%) of seropositive samples. Ticks collected from culled deer within seropositive regions were tested for viral RNA; 5 of 2,041 ticks tested positive by LIV/TBEV real-time reverse transcription PCR, all from within the Thetford Forest area. From 1 tick, we identified a full-length genomic sequence of TBEV. Thus, using deer as sentinels revealed a potential TBEV focus in the United Kingdom. This detection of TBEV genomic sequence in UK ticks has important public health implications, especially for undiagnosed encephalitis.
Tick-borne encephalitis was limited to northeast portions of Italy. We report in Lombardy, a populous region in the northwest, a chamois displaying clinical signs of tickborne encephalitis virus that ...had multiple virus-positive ticks attached, as well as a symptomatic man. Further, we show serologic evidence of viral circulation in the area.
X‐ray imaging of virus particles at the European XFEL could eventually allow their complete structures to be solved, potentially approaching the resolution of other structural virology methods. To ...achieve this ambitious goal with today's technologies, about 1 ml of purified virus suspension containing at least 1012 particles per millilitre is required. Such large amounts of concentrated suspension have never before been obtained for enveloped viruses. Tick‐borne encephalitis virus (TBEV) represents an attractive model system for the development of enveloped virus purification and concentration protocols, given the availability of large amounts of inactivated virus material provided by vaccine‐manufacturing facilities. Here, the development of a TBEV vaccine purification and concentration scheme is presented combined with a quality‐control protocol that allows substantial amounts of highly concentrated non‐aggregated suspension to be obtained. Preliminary single‐particle imaging experiments were performed for this sample at the European XFEL, showing distinct diffraction patterns.
A purification and concentration scheme for the tick‐borne encephalitis virus (TBEV) vaccine was developed along with a quality‐control protocol that enabled substantial amounts of highly concentrated non‐aggregated suspension to be produced. This approach allowed single‐particle imaging experiments to be conducted for this sample at the European XFEL, which resulted in distinct patterns of diffraction. In order to illustrate the advantages of the proposed protocols, the cryo‐EM structure of TBEV has been determined.
Tick-borne encephalitis virus (TBEV) is an emerging pathogen that was first detected in ticks and humans in the Netherlands in 2015 (ticks) and 2016 (humans). To learn more about its distribution and ...prevalence in the Netherlands, we conducted large-scale surveillance in ticks and rodents during August 2018-September 2020. We tested 320 wild rodents and >46,000 ticks from 48 locations considered to be at high risk for TBEV circulation. We found TBEV RNA in 3 rodents (0.9%) and 7 tick pools (minimum infection rate 0.02%) from 5 geographically distinct foci. Phylogenetic analyses indicated that 3 different variants of the TBEV-Eu subtype circulate in the Netherlands, suggesting multiple independent introductions. Combined with recent human cases outside known TBEV hotspots, our data demonstrate that the distribution of TBEV in the Netherlands is more widespread than previously thought.
Flaviviruses comprise a number of mosquito‐ or tick‐transmitted human pathogens of global public health importance. Advances in structural biology techniques have contributed substantially to our ...current understanding of the life cycle of these small enveloped RNA viruses and led to deep insights into details of virus assembly, maturation and cell entry. In addition to large‐scale conformational changes and oligomeric rearrangements of envelope proteins during these processes, there is increasing evidence that smaller‐scale protein dynamics (referred to as virus “breathing”) can confer extra flexibility to these viruses for the fine‐tuning of their interactions with the immune system and possibly with cellular factors they encounter in their complex ecological cycles in arthropod and vertebrate hosts. In this review, we discuss how work with tick‐borne encephalitis virus has extended our view on flavivirus breathing, leading to the identification of a novel mechanism of antibody‐mediated infection enhancement and demonstrating breathing intermediates of the envelope protein in the process of membrane fusion. These data are discussed in the context of other flaviviruses and the perspective of a potential role of virus breathing to cope with the requirements of adaptation and replication in evolutionarily very different hosts.
Small‐scale dynamics of the major envelope protein E of flaviviruses (“virus breathing”) together with binding of specific antibodies can promote fusion‐loop exposure and insertion into plasma membranes of target cells, providing the basis for a special mechanism of antibody‐mediated enhanced infection. Upon cellular uptake by endocytosis, dynamic “breathing” intermediates are functionally important for the structural conversions of E into a post‐fusion conformation to drive membrane fusion in the endosome.
To increase knowledge of tick-borne encephalitis virus (TBEV) circulation in the Netherlands, we conducted serosurveillance in roe deer (Capreolus capreolus) during 2017 and compared results with ...those obtained during 2010. Results corroborate a more widespread occurrence of the virus in 2017. Additional precautionary public health measures have been taken.
Information on febrile illness caused by tick-borne encephalitis virus (TBEV) without central nervous system involvement is limited. We characterized 98 patients who had TBEV RNA in their blood but ...no central nervous system involvement at the time of evaluation. Median duration of illness was 7 days; 37 (38%) patients were hospitalized. The most frequent findings were malaise or fatigue (98%), fever (97%), headache (86%), and myalgias (54%); common laboratory findings were leukopenia (88%), thrombocytopenia (59%), and abnormal liver test results (63%). During the illness, blood leukocyte counts tended to improve, whereas thrombocytopenia and liver enzymes tended to deteriorate. At the time of positive PCR findings, 0/98 patients had serum IgG TBEV and 7 serum IgM TBEV; all patients later seroconverted. Viral RNA load was higher in patients with more severe illness but did not differ substantially in relation to several other factors. Illness progressed to tick-borne encephalitis in 84% of patients within 18 days after defervescence.
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