Categorization systems for tick-borne encephalitis virus (TBEV) infection lack consistency in classifying disease severity. To evaluate the need for a standard, consensus-based categorisation system for TBEV infection across subtypes, we gathered an expert panel of clinicians and scientists with diverse expertise in TBEV infection. Consensus was sought using the Delphi technique, which consisted of 2 web-based survey questionnaires and a final, virtual, consensus-building exercise. Ten panellists representing 8 European countries participated in the Delphi exercise, with specialities in neurology, infectious disease, paediatrics, immunology, virology, and epidemiology. Panellists reached unanimous consensus on the need for a standardised, international categorisation system to capture both clinical presentation and severity of TBEV infection. Ideally, such a system should be feasible for use at bedside, be clear and easy to understand, and capture both the acute and follow-up phases of TBEV infection. Areas requiring further discussion were (1) the timepoints at which assessments should be made and (2) whether there should be a separate system for children. This Delphi panel study found that a critical gap persists in the absence of a feasible and practical classification system for TBEV infection. Specifically, the findings of our Delphi exercise highlight the need for the development of a user-friendly classification system that captures the acute and follow-up (i.e., outcome) phases of TBEV infection and optimally reflects both clinical presentation and severity. Development of a clinical categorisation system will enhance patient care and foster comparability among studies, thereby supporting treatment development, refining vaccine strategies, and fortifying public health surveillance.

• MeSH
• delfská metoda * MeSH
• klíšťová encefalitida * epidemiologie   virologie   diagnóza   MeSH
• konsensus MeSH
• lidé MeSH
• viry klíšťové encefalitidy * klasifikace   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Tick-borne encephalitis virus (TBEV) is a significant threat to human health. The virus causes potentially fatal disease of the central nervous system (CNS), for which no treatments are available. TBEV infected individuals display a wide spectrum of neuronal disease, the determinants of which are undefined. Changes to host metabolism and virus-induced immunity have been postulated to contribute to the neuronal damage observed in infected individuals. In this study, we evaluated the cytokine, chemokine, and metabolic alterations in the cerebrospinal fluid (CSF) of symptomatic patients infected with TBEV presenting with meningitis or encephalitis. Our aim was to investigate the host immune and metabolic responses associated with specific TBEV infectious outcomes. METHODS: CSF samples of patients with meningitis (n = 27) or encephalitis (n = 25) were obtained upon consent from individuals hospitalised with confirmed TBEV infection in Brno. CSF from uninfected control patients was also collected for comparison (n = 12). A multiplex bead-based system was used to measure the levels of pro-inflammatory cytokines and chemokines. Untargeted metabolomics followed by bioinformatics and integrative omics were used to profile the levels of metabolites in the CSF. Human motor neurons (hMNs) were differentiated from induced pluripotent stem cells (iPSCs) and infected with the highly pathogenic TBEV-Hypr strain to profile the role(s) of identified metabolites during the virus lifecycle. Virus infection was quantified via plaque assay. RESULTS: Significant differences in proinflammatory cytokines (IFN-α2, TSLP, IL-1α, IL-1β, GM-CSF, IL-12p40, IL-15, and IL-18) and chemokines (IL-8, CCL20, and CXCL11) were detected between neurological-TBEV and control patients. A total of 32 CSF metabolites differed in TBE patients with meningitis and encephalitis. CSF S-Adenosylmethionine (SAM), Fructose 1,6-bisphosphate (FBP1) and Phosphoenolpyruvic acid (PEP) levels were 2.4-fold (range ≥ 2.3-≥3.2) higher in encephalitis patients compared to the meningitis group. CSF urocanic acid levels were significantly lower in patients with encephalitis compared to those with meningitis (p = 0.012209). Follow-up analyses showed fluctuations in the levels of O-phosphoethanolamine, succinic acid, and L-proline in the encephalitis group, and pyruvic acid in the meningitis group. TBEV-infection of hMNs increased the production of SAM, FBP1 and PEP in a time-dependent manner. Depletion of the metabolites with characterised pharmacological inhibitors led to a concentration-dependent attenuation of virus growth, validating the identified changes as key mediators of TBEV infection. CONCLUSIONS: Our findings reveal that the neurological disease outcome of TBEV infection is associated with specific and dynamic metabolic signatures in the cerebrospinal fluid. We describe a new in vitro model for in-depth studies of TBEV-induced neuropathogenesis, in which the depletion of identified metabolites limits virus infection. Collectively, this reveals new biomarkers that can differentiate and predict TBEV-associated neurological disease. Additionally, we have identified novel therapeutic targets with the potential to significantly improve patient outcomes and deepen our understanding of TBEV pathogenesis.

• MeSH
• cytokiny mozkomíšní mok   MeSH
• dospělí MeSH
• klíšťová encefalitida * mozkomíšní mok   metabolismus   MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolom * fyziologie   MeSH
• metabolomika MeSH
• mladý dospělý MeSH
• neurony * metabolismus   virologie   MeSH
• senioři MeSH
• viry klíšťové encefalitidy * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: For many years, syphilis treatment was considered straightforward due to the universal susceptibility of Treponema pallidum subsp. pallidum (TPA) to penicillin antibiotics. METHODS: Penicillin-binding protein genes from a ceftriaxone treatment failure T. pallidum isolate were assessed, and the introduction of identified mutations into two laboratory strains via natural competence was aimed for, followed by in vitro analysis of antibiotic susceptibility of the recombinants. RESULTS: TPA from the ceftriaxone treatment failure case contained A1873G and G2122A mutations in the TP0705 gene. Introduction of the A1873G mutation into laboratory strains DAL-1 and SS14 resulted in partial resistance to ceftriaxone and penicillin G in vitro. Furthermore, in silico analyses revealed that the majority of contemporary TPA SS14-like strains harbors this mutation and are thus partially resistant to ceftriaxone and penicillin G. CONCLUSIONS: This finding indicates that TPA strains accumulate mutations that increase their resistance to β-lactam antibiotics. Alternative approaches for controlling syphilis will be needed, including the development of the syphilis vaccine.

• 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

• MeSH
• lidé MeSH
• novorozenec MeSH
• vrozená syfilis * diagnóza   epidemiologie   patologie   terapie   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• Borrelia burgdorferi komplex klasifikace   patogenita   MeSH
• ceftriaxon farmakologie   terapeutické užití   MeSH
• dítě MeSH
• doxycyklin farmakologie   terapeutické užití   MeSH
• erythema chronicum migrans diagnóza   etiologie   klasifikace   MeSH
• lidé MeSH
• lymeská nemoc * diagnóza   farmakoterapie   komplikace   prevence a kontrola   MeSH
• lymská neuroborelióza diagnóza   komplikace   mikrobiologie   MeSH
• protilátky bakteriální analýza   klasifikace   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• přehledy MeSH

Matrix metalloproteinases (MMPs) play an important role in central nervous system infections. We analysed the levels of 8 different MMPs in the cerebrospinal fluid (CSF) of 89 adult patients infected with tick-borne encephalitis (TBE) virus and compared them with the levels in a control group. MMP-9 was the only MMP that showed significantly increased CSF levels in TBE patients. Serum MMP-9 levels were subsequently measured in 101 adult TBE patients at various time points during the neurological phase of TBE and at follow-up. In addition, serum MMP-9 was analysed in 37 paediatric TBE patients. Compared with control levels, both paediatric and adult TBE patients had significantly elevated serum MMP-9 levels. In most adult patients, serum MMP-9 levels peaked at hospital admission, with higher serum MMP-9 levels observed in patients with encephalitis than in patients with meningitis. Elevated serum MMP-9 levels were observed throughout hospitalisation but decreased to normal levels at follow-up. Serum MMP-9 levels correlated with clinical course, especially in patients heterozygous for the single-nucleotide polymorphism rs17576 (A/G; Gln279Arg) in the MMP9 gene. The results highlight the importance of MMP-9 in the pathogenesis of TBE and suggest that serum MMP-9 may serve as a promising bioindicator of TBE in both paediatric and adult TBE patients.

• MeSH
• biologické markery MeSH
• dítě MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus MeSH
• klíšťová encefalitida * diagnóza   mozkomíšní mok   MeSH
• lidé MeSH
• matrixová metaloproteinasa 9 genetika   MeSH
• viry klíšťové encefalitidy * genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Tularemie patří mezi celosvětově rozšířené zoonózy a i přes její relativně nízkou incidenci v našich podmínkách by neměla být v rámci diferenciální diagnostiky opomíjena. V popisované kazuistice bychom chtěli upozornit na klíště jako možný vektor přenosu ulceroglandulární formy tularemie u dětí a současně vyzvednout výhody metody PCR, která může být použita jako časná a spolehlivá metoda detekce obtížně kultivovatelné bakterie Francisella tularensis.

Tularaemia is a widespread zoonosis, which should be considered in differential diagnostics of lymphadenopathy despite of relatively low incidence of the disease. In the presented case we would like to point out a tick bite as a possible way of transmission of an ulceroglandular form of tularaemia in children as well as underline PCR method as an early and reliable form of detection.

• MeSH
• antibakteriální látky MeSH
• ciprofloxacin aplikace a dávkování   terapeutické užití   MeSH
• Francisella tularensis patogenita   MeSH
• lidé MeSH
• lymfadenopatie chirurgie   etiologie   MeSH
• nemoci přenášené klíšťaty diagnóza   farmakoterapie   patologie   MeSH
• obličej abnormality   chirurgie   patologie   MeSH
• předškolní dítě MeSH
• tularemie * diagnóza   farmakoterapie   patologie   MeSH
• zoonózy diagnóza   farmakoterapie   patologie   MeSH
• Check Tag
• lidé MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Tick-borne encephalitis (TBE) is a neuroviral disease that ranges in severity from a mild febrile illness to a severe and life-threatening meningoencephalitis or encephalomyelitis. There is increasing evidence that susceptibility to tick-borne encephalitis virus (TBEV)-induced disease and its severity are largely influenced by host genetic factors, in addition to other virus- and host-related factors. In this study, we investigated the contribution of selected single nucleotide polymorphisms (SNPs) in innate immunity genes to predisposition to TBE in humans. More specifically, we investigated a possible association between SNPs rs304478 and rs303212 in the gene Interferon Induced Protein With Tetratricopeptide Repeats 1 (IFIT1), rs7070001 and rs4934470 in the gene Interferon Induced Protein With Tetratricopeptide Repeats 2 (IFIT2), and RIG-I (Retinoic acid-inducible gene I) encoding gene DDX58 rs311795343, rs10813831, rs17217280 and rs3739674 SNPs with predisposition to TBE in population of the Czech Republic, where TBEV is highly endemic. Genotypic and allelic frequencies for these SNPs were analyzed in 247 nonimmunized TBE patients and compared with 204 control subjects. The analysis showed an association of IFIT1 rs304478 SNP and DDX58 rs3739674 and rs17217280 SNPs with predisposition to TBE in the Czech population indicating novel risk factors for clinical TBE but not for disease severity. These results also highlight the role of innate immunity genes in TBE pathogenesis.

• MeSH
• genotyp MeSH
• interferony genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• klíšťová encefalitida * genetika   epidemiologie   MeSH
• lidé MeSH
• přirozená imunita genetika   MeSH
• viry klíšťové encefalitidy * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Klíšťová encefalitida (KE) je v České republice nejvýznamnější virovou neuroinfekcí člověka. Klinický průběh KE může být různě závažný – od lehkého horečnatého či chřipkovitého onemocnění, přes meningitidy, či vážné a potenciálně smrtelné meningoencefalitidy nebo encefalomyelitidy. Hlavním cílem tohoto kolaborativního biomedicínského projektu je identifikace genetických faktorů, které ovlivňují závažnost KE u pacientů v ČR a určit vztah různých klinických forem KE k expresi specifických biomarkerů přítomných v séru a mozkomíšním moku. Úloha určitého genotypu bude následně studována detailněji s využitím animálních modelů KE. Předkládaná genetická, imunologická a biochemická studie odhalí nové poznatky o biologických mechanismech zapojených v patogenezi KE a po doplnění o klinická data přinese nové možnosti a nástroje, jak zhodnotit prognózu u konkrétního pacienta a zvolit podle toho vhodný terapeutický režim.; Tick-borne encephalitis (TBE) is the most important human viral neuroinfection in the Czech Republic. TBE severity can range from an asymptomatic or mild flu-like disease to meningitis or severe and potentially fatal meningoencephalitis or encephalomyelitis. The ultimate goal of this collaborative biomedical research project is to identify genetic factors that influence severity of TBE in Czech patients, determine relationship between different clinical forms of TBE with the expression of specific biomarkers, present in serum and cerebrospinal fluid. Moreover, the role of host genetic background in TBE pathogenesis will be investigated in more detail using animal models of the disease. The genetic, immunological and biochemical investigations will reveal new knowledge about the biological mechanisms of pathogenesis of TBE, and the clinical investigation will provide a very useful tool in terms of estimating patients’ prognosis and adequate use of therapeutic measures.

• Klíčová slova
• Genetická predispozice, Genetic predisposition, imunitní odpověď, immune response, tick-borne encephalitis, imunopatologie, Immunopathology, klíšťová encefalitida, virus klíšťové encefalitidy, neuroinfekce, tick-borne encephalitis virus, neuroinfection,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR