Tick-borne encephalitis (TBE) and Lyme neuroborreliosis (LNB), the most common tick-borne diseases of the central nervous system in Central Europe, are frequently associated with pareses. The aim of this study was to characterise paretic complications in patients with TBE and LNB, including their severity, persistence and impact on the patients' quality of life. Our retrospective observational study included patients with aseptic CNS infection due to TBE virus or Borrelia burgdorferi sensu lato. Paretic complications were evaluated in the acute phase and the patients were followed up until complete regression or long-term stabilisation of any neurological deficit. The severity of the neurological deficit was graded according to the modified Rankin Scale (mRS). A total of 823 patients (582 with TBE, 241 with LNB) was included. Paretic complications were diagnosed in 63 TBE patients (10.8 %) and in 147 LNB patients (61.0 %). In TBE, the most common neurological deficit was brachial plexus paresis in 21 patients (33 %) and bulbar symptoms in 18 patients (29 %). In LNB patients, facial nerve palsy was the most frequent neurological deficit (117patients; 79.6 %), followed by lower limb paresis in 23 patients (15.6 %). Forty-nine TBE patients and 134 LNB paretic patients completed follow-up. Paresis resolved within 3 weeks in 16 TBE patients (33 %) and 53 LNB patients (39.5 %), but the proportion of patients with paresis persisting for more than 12 months was significantly higher in TBE (34.7 vs. 3.7 %, p < 0.001). The mean mRS was significantly higher in TBE paretic patients compared to LNB (p < 0.001). Paretic complications are significantly more common in LNB than in TBE but pareses associated with TBE last longer than in LNB and considerably reduce the quality of life of patients. Prevention remains the only way to influence the long-term motor deficits of TBE.
- MeSH
- klíšťová encefalitida * komplikace epidemiologie diagnóza MeSH
- kvalita života MeSH
- lidé MeSH
- lymská neuroborelióza * komplikace epidemiologie diagnóza MeSH
- paréza etiologie komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- Geografické názvy
- Česká republika MeSH
Viral infection may represent a stress condition to the host cell. Cells react to it by triggering the defence programme to restore homeostasis and these events may in turn impact the viral replication. The knowledge about tick-borne encephalitis virus (TBEV) infection-associated stress is limited. Here we investigated the interplay between TBEV infection and stress pathways in PMJ2-R mouse macrophage cell line, as macrophages are the target cells in early phases of TBEV infection. First, to determine how stress influences TBEV replication, the effect of stress inducers H2O2 and tunicamycin (TM) was tested. Viral multiplication was decreased in the presence of both stress inducers suggesting that the stress and cellular stress responses restrict the virus replication. Second, we investigated the induction of oxidative stress and endoplasmic reticulum (ER) stress upon TBEV infection. The level of oxidative stress was interrogated by measuring the reactive oxygen species (ROS). ROS were intermittently increased in infected cells at 12 hpi and at 72 hpi. As mitochondrial dysfunction may result in increased ROS level, we evaluated the mitochondrial homeostasis by measuring the mitochondrial membrane potential (MMP) and found that TBEV infection induced the hyperpolarization of MMP. Moreover, a transient increase of gene expression of stress-induced antioxidative enzymes, like p62, Gclm and Hmox1, was detected. Next, we evaluated the ER stress upon TBEV infection by analysing unfolded protein responses (UPR). We found that infection induced gene expression of two general sensors BiP and CHOP and activated the IRE1 pathway of UPR. Finally, since the natural transmission route of TBEV from its tick vector to the host is mediated via tick saliva, the impact of tick saliva from Ixodes ricinus on stress pathways in TBEV-infected cells was tested. We observed only marginal potentiation of UPR pathway. In conclusion, we found that TBEV infection of PMJ2-R cells elicits the changes in redox balance and triggers cellular stress defences, including antioxidant responses and the IRE1 pathway of UPR. Importantly, our results revealed the negative effect of stress-evoked events on TBEV replication and only marginal impact of tick saliva on stress cellular pathways.
- MeSH
- buněčné linie MeSH
- klíšťová encefalitida * MeSH
- myši MeSH
- peroxid vodíku metabolismus MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- replikace viru MeSH
- viry klíšťové encefalitidy * genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Tick-borne encephalitis (TBE) virus (TBEV) is transmitted to humans via tick bites. Infection is benign in >90% of the cases but can cause mild (<5%), moderate (<4%), or severe (<1%) encephalitis. We show here that ∼10% of patients hospitalized for severe TBE in cohorts from Austria, Czech Republic, and France carry auto-Abs neutralizing IFN-α2, -β, and/or -ω at the onset of disease, contrasting with only ∼1% of patients with moderate and mild TBE. These auto-Abs were found in two of eight patients who died and none of 13 with silent infection. The odds ratios (OR) for severe TBE in individuals with these auto-Abs relative to those without them in the general population were 4.9 (95% CI: 1.5-15.9, P < 0.0001) for the neutralization of only 100 pg/ml IFN-α2 and/or -ω, and 20.8 (95% CI: 4.5-97.4, P < 0.0001) for the neutralization of 10 ng/ml IFN-α2 and -ω. Auto-Abs neutralizing type I IFNs accounted for ∼10% of severe TBE cases in these three European cohorts.
- MeSH
- autoprotilátky * imunologie MeSH
- dospělí MeSH
- interferon typ I * imunologie MeSH
- klíšťová encefalitida * imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- neutralizující protilátky * imunologie MeSH
- senioři MeSH
- viry klíšťové encefalitidy imunologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Rakousko MeSH
V České republice je hlášena nejvyšší incidence klíšťové encefalitidy ze všech zemí Evropské unie, přesto je proočkovanost nejnižší ze všech endemických zemí. V roce 2020 došlo k vzestupu počtu hlášených případů klíšťové encefalitidy na rekordních 856 případů odpovídající incidenci 7,98 na 100 000 obyvatel. Nejpostiženější věkovou skupinou za rok 2020 byla věková skupina 60–64 let, ale zdvojnásobení počtu hlášených onemocnění oproti předešlému roku bylo pozorováno i u nejmenších a předškolních dětí. V roce 2021 byl nahlášen mírný pokles počtu případů na 594, za rok 2022 to bylo opět 710 případů a v roce 2023 celkem 514 případů. Porovnáním posledních 5 let do roku 2022 s obdobím předchozích 5 let došlo k nárůstu počtu hlášených případů onemocnění o 38 %. Klinické projevy klíšťové encefalitidy u dětí jsou méně typické v porovnání s dospělými, většinou bývají mírnější, některá onemocnění u dětí nejsou diagnostikována. Z rostoucího počtu zahraničních studií vyplývá, že se ani u dětí nejedná o benigní onemocnění. U 12 až 69 % dětí dochází ke kognitivním poruchám a bolestem hlavy. Očkování je specifickou prevencí proti onemocnění klíšťovou encefalitidou, k dispozici je inaktivovaná vakcína s vysokými parametry bezpečnosti a účinnosti. Proočkovanost v České republice v roce 2023 stoupla na 40 %, nejvýraznější nárůst byl zaznamenán u věkových kohort nad 50 let, a to především vlivem dopadu zavedené úhrady z veřejného zdravotního pojištění od roku 2022. Dopady onemocnění a nárůst počtu případů v nejmladších věkových kategoriích u dětí spolu s nízkou proočkovaností by měly vést k aktivní nabídce očkování již v nižších věkových kategoriích u dětí.
The Czech Republic has the highest reported incidence of tick-borne encephalitis of all countries in the European Union, yet the vaccination rate is the lowest of all endemic countries. In 2020, the number of reported cases of tick-borne encephalitis increased to a record 856 cases and a corresponding incidence of 7.98 per 100 thousand inhabitants. The most affected age group in 2020 was the 60-64 age group, but a doubling of the number of reported diseases compared to the previous year was also observed in the youngest and pre-school children. In 2021, a slight decrease in the number of cases was reported to 594, in 2022 it was again 710 cases and in 2023 a total of 514 cases. Comparing the last 5 years to 2022 with the period of the previous 5 years, there was a 38 % increase in the number of reported cases of the disease. Clinical manifestations of tick-borne encephalitis in children are less typical compared to adults, they are usually milder, some diseases in children are not diagnosed. A growing number of foreign studies show that it is not a benign disease even in children. Between 12 % and 69 % of children experience cognitive impairment and headaches. Vaccination is a specific prevention against tick-borne encephalitis, an inactivated vaccine with high safety and efficacy parameters is available. The vaccination rate in the Czech Republic rose to 40% in 2023, with the most significant increase recorded in age cohorts over 50, mainly due to the impact of the introduction of reimbursement in public health insurance from 2022. The impact of the disease and the increase in the number of cases in the youngest age categories in children, together with low vaccination coverage, should lead to an active offer of vaccination in children at a younger age.
- MeSH
- dítě MeSH
- klíšťová encefalitida * epidemiologie prevence a kontrola MeSH
- lidé MeSH
- vakcinace * statistika a číselné údaje MeSH
- vakcíny MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Geografické názvy
- Česká republika MeSH
Tick-borne encephalitis virus (TBEV) targets the central nervous system (CNS), leading to potentially severe neurological complications. The neurovascular unit plays a fundamental role in the CNS and in the neuroinvasion of TBEV. However, the role of human brain pericytes, a key component of the neurovascular unit, during TBEV infection has not yet been elucidated. In this study, TBEV infection of the primary human brain perivascular pericytes was investigated with highly virulent Hypr strain and mildly virulent Neudoerfl strain. We used Luminex assay to measure cytokines/chemokines and growth factors. Both viral strains showed comparable replication kinetics, peaking at 3 days post infection (dpi). Intracellular viral RNA copies peaked at 6 dpi for Hypr and 3 dpi for Neudoerfl cultures. According to immunofluorescence staining, only small proportion of pericytes were infected (3% for Hypr and 2% for Neudoerfl), and no cytopathic effect was observed in the infected cells. In cell culture supernatants, IL-6 production was detected at 3 dpi, together with slight increases in IL-15 and IL-4, but IP-10, RANTES and MCP-1 were the main chemokines released after TBEV infection. These chemokines play key roles in both immune defense and immunopathology during TBE. This study suggests that pericytes are an important source of these signaling molecules during TBEV infection in the brain.
- MeSH
- chemokin CCL5 * metabolismus MeSH
- chemokin CXCL10 * metabolismus MeSH
- cytokiny metabolismus MeSH
- klíšťová encefalitida * virologie metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- mozek * virologie metabolismus patologie MeSH
- pericyty * virologie metabolismus MeSH
- replikace viru MeSH
- viry klíšťové encefalitidy * fyziologie patogenita MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- symptomatická léčba,
- MeSH
- hlášení nemocí MeSH
- incidence MeSH
- klíště růst a vývoj virologie MeSH
- klíšťová encefalitida * diagnóza epidemiologie komplikace prevence a kontrola MeSH
- lidé MeSH
- repelenty proti hmyzu MeSH
- vakcinace * metody MeSH
- viry klíšťové encefalitidy klasifikace patogenita MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Česká republika MeSH
Background: Tick-borne encephalitis (TBE) is caused by the tick-borne encephalitis virus (TBEV). TBEV infection can cause symptoms of central nervous system (CNS) inflammation and result in severe consequences including death. TBE is an increasing health threat in the Czech Republic and elsewhere in Europe. In 2020, 23% of 3734 TBE cases reported to the European Centre for Disease Prevention and Control were from the Czech Republic. TBE vaccination is universally recommended in the Czech Republic, but a full analysis of TBE vaccine effectiveness (VE) in the Czech Republic has not been published. Methods: TBE is a notifiable disease in the Czech Republic with mandatory reporting of cases (i.e., laboratory-confirmed TBEV infected patient with symptoms of CNS inflammation) and vaccination history to public health authorities. TBE VE was estimated using the screening method utilizing public health surveillance data from 2018 to 2022 and online household surveys of the general population on TBE vaccine uptake conducted in 2019-2022. Results: In 2018-2022, 3648 TBE cases were reported in the Czech Republic; 98.1% (3105/3166) of TBE cases with known vaccination history were unvaccinated. Among 42,671 persons surveyed from the general population who had known TBE vaccination history, 66.5% were unvaccinated. VE against TBE was 97.6% (95% confidence interval 95.7-98.7). When stratified by age group, VE was 97.1% (88.4-99.3) in 1-15 years of age, 97.9% (95.3-99.0) in 16-59 years of age, and 96.9% (90.5-99.0) in ≥60 years of age. TBE vaccination averted an estimated 1020 TBE cases in the Czech Republic from 2018 to 2022. Conclusions: This first published study with a full analysis of TBE VE in the Czech Republic showed that vaccination was highly effective for the prevention of TBE including in children, an age group with increasing TBE disease burden. Vaccination averted hundreds of TBE cases and hospitalizations despite the relatively low compliance with TBE vaccine recommendations. To prevent additional TBE cases in the Czech Republic, enhanced efforts to increase TBE vaccine uptake are needed.
- MeSH
- dítě MeSH
- dospělí MeSH
- klíšťová encefalitida * prevence a kontrola epidemiologie MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- senioři MeSH
- vakcinace * MeSH
- virové vakcíny * aplikace a dávkování MeSH
- viry klíšťové encefalitidy * imunologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Tick-borne encephalitis virus (TBEV) is a neurotropic orthoflavivirus responsible for severe infections of the central nervous system. Although neurons are predominantly targeted, specific involvement of microglia in pathogenesis of TBE is not yet fully understood. In this study, the susceptibility of human microglia to TBEV is investigated, focusing on productive infection and different immune responses of different viral strains. We investigated primary human microglia and two immortalized microglial cell lines exposed to three TBEV strains (Hypr, Neudörfl and 280), each differing in virulence. Our results show that all microglia cultures tested support long-term productive infections, regardless of the viral strain. In particular, immune response varied significantly with the viral strain, as shown by the differential secretion of cytokines and chemokines such as IP-10, MCP-1, IL-8 and IL-6, quantified using a Luminex 48-plex assay. The most virulent strain triggered the highest cytokine induction. Electron tomography revealed substantial ultrastructural changes in the infected microglia, despite the absence of cytopathic effects. These findings underscore the susceptibility of human microglia to TBEV and reveal strain-dependent variations in viral replication and immune responses, highlighting the complex role of microglia in TBEV-induced neuropathology and contribute to a deeper understanding of TBE pathogenesis and neuroinflammation.
- MeSH
- buněčné linie MeSH
- cytokiny * metabolismus MeSH
- klíšťová encefalitida * virologie patologie imunologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- mikroglie * virologie imunologie patologie MeSH
- neurozánětlivé nemoci virologie patologie imunologie MeSH
- replikace viru MeSH
- viry klíšťové encefalitidy * patogenita fyziologie imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Tick-borne encephalitis virus (TBEV) is a tick-borne flavivirus that induces severe central nervous system disorders. It has recently raised concerns due to an expanding geographical range and increasing infection rates. Existing vaccines, though effective, face low coverage rates in numerous TBEV endemic regions. Our previous work demonstrated the immunogenicity and full protection afforded by a TBEV vaccine based on virus-like particles (VLPs) produced in Leishmania tarentolae cells in immunization studies in a mouse model. In the present study, we explored the impact of adjuvants (AddaS03TM, Alhydrogel®+MPLA) and administration routes (subcutaneous, intramuscular) on the immune response. Adjuvanted groups exhibited significantly enhanced antibody responses, higher avidity, and more balanced Th1/Th2 response. IFN-γ responses depended on the adjuvant type, while antibody levels were influenced by both adjuvant and administration routes. The combination of Leishmania-derived TBEV VLPs with Alhydrogel® and MPLA via intramuscular administration emerged as a highly promising prophylactic vaccine candidate, eliciting a robust, balanced immune response with substantial neutralization potential.
- MeSH
- adjuvancia imunologická * aplikace a dávkování MeSH
- adjuvantní vakcína aplikace a dávkování MeSH
- imunogenicita vakcíny MeSH
- injekce intramuskulární MeSH
- interferon gama imunologie MeSH
- klíšťová encefalitida * prevence a kontrola imunologie MeSH
- Leishmania * imunologie MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- neutralizující protilátky krev imunologie MeSH
- protilátky virové * krev imunologie MeSH
- syntetické vakcíny * imunologie aplikace a dávkování MeSH
- Th1 buňky imunologie MeSH
- virové vakcíny * imunologie aplikace a dávkování MeSH
- viry klíšťové encefalitidy * imunologie MeSH
- VLP vakcíny * imunologie aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
