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.

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.

• 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

The presence of a non-structural protein 1 (NS1) in tick-borne encephalitis (TBE) vaccines and the possible induction of an NS1-specific immune response in vaccinated individuals remains a somewhat controversial topic. Previously, we detected the presence of NS1 in the Encepur TBE vaccine by mass spectrometry and found the induction of NS1-specific IgG antibodies in mice vaccinated with the FSME-Immun TBE vaccine. Here, in this follow-up study, we examined the dynamics and extent of the NS1-specific IgG response in mice vaccinated with these two vaccines in more detail and compared it with the IgG response to the whole virus (WV). Mice were vaccinated at two-week intervals with a total of six doses of each vaccine, and levels of IgG antibodies to TBE virus WV and NS1 were measured by ELISA after each dose. Both vaccines elicited a robust anti-WV IgG response after two doses. The Encepur vaccine did not elicit NS1-specific IgG even after all six doses. In contrast, the FSME-Immun vaccine triggered the production of NS1-specific IgG after four doses. The results indicate that FSME-Immun is the only vaccine that elicits an NS1-specific antibody response in mice. However, compared to WV-specific IgG, the NS1-specific response is weaker, and a higher number of doses is required to induce detectable levels of NS1-specific IgG antibodies.

• Publikační typ
• časopisecké články MeSH

Tick-borne encephalitis (TBE) is a serious viral neuroinfection affecting humans in large areas of Europe and Asia. TBE can occur at any age, but only a few reports of TBE in infants younger than 1 year have been published. Here, we report a case of severe TBE in an 8.5-month-old boy presenting with seizures at the beginning of the neurological phase.

• Publikační typ
• kazuistiky MeSH

Tick-borne encephalitis (TBE) virus is a major cause of central nervous system infections in endemic countries. Here, we present clinical and laboratory characteristics of a large international cohort of patients with confirmed TBE using a uniform clinical protocol. Patients were recruited in eight centers from six European countries between 2010 and 2017. A detailed description of clinical signs and symptoms was recorded. The obtained information enabled a reliable classification in 553 of 555 patients: 207 (37.3%) had meningitis, 273 (49.2%) meningoencephalitis, 15 (2.7%) meningomyelitis, and 58 (10.5%) meningoencephalomyelitis; 41 (7.4%) patients had a peripheral paresis of extremities, 13 (2.3%) a central paresis of extremities, and 25 (4.5%) had single or multiple cranial nerve palsies. Five (0.9%) patients died during acute illness. Outcome at discharge was recorded in 298 patients. Of 176 (59.1%) patients with incomplete recovery, 80 (27%) displayed persisting symptoms or signs without recovery expectation. This study provides further evidence that TBE is a severe disease with a large proportion of patients with incomplete recovery. We suggest monitoring TBE in endemic European countries using a uniform protocol to record the full clinical spectrum of the disease.

• Publikační typ
• časopisecké články MeSH

Vaccination against tick-borne encephalitis (TBE) is based on the use of formalin-inactivated, culture-derived whole-virus vaccines. Immune response following vaccination is primarily directed to the viral envelope (E) protein, the major viral surface antigen. In Europe, two TBE vaccines are available in adult and pediatric formulations, namely FSME-IMMUN® (Pfizer) and Encepur® (GlaxoSmithKline). Herein, we analyzed the content of these vaccines using mass spectrometry (MS). The MS analysis revealed that the Encepur vaccine contains not only proteins of the whole virus particle, but also viral non-structural protein 1 (NS1). MS analysis of the FSME-IMMUN vaccine failed due to the high content of human serum albumin used as a stabilizer in the vaccine. However, the presence of NS1 in FSME-IMMUN was confirmed by immunization of mice with six doses of this vaccine, which led to a robust anti-NS1 antibody response. NS1-specific Western blot analysis also detected anti-NS1 antibodies in sera of humans who received multiple doses of either of these two vaccines; however, most vaccinees who received ≤3 doses were negative for NS1-specific antibodies. The contribution of NS1-specific antibodies to protection against TBE was demonstrated by immunization of mice with purified NS1 antigen, which led to a significant (p < 0.01) prolongation of the mean survival time after lethal virus challenge. This indicates that stimulation of anti-NS1 immunity by the TBE vaccines may increase their protective effect.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: Tick-borne encephalitis (TBE) is a severe neuropathological disorder caused by tick-borne encephalitis virus (TBEV). Brain TBEV infection is characterized by extensive pathological neuroinflammation. The mechanism by which TBEV causes CNS destruction remains unclear, but growing evidence suggests that it involves both direct neuronal damage by the virus infection and indirect damage caused by the immune response. Here, we aimed to examine the TBEV-infection-induced innate immune response in mice and in human neural cells. We also compared cytokine/chemokine communication between naïve and infected neuronal cells and astrocytes. METHODS: We used a multiplexed Luminex system to measure multiple cytokines/chemokines and growth factors in mouse serum samples and brain tissue, and in human neuroblastoma cells (SK-N-SH) and primary cortical astrocytes (HBCA), which were infected with the highly pathogenic TBEV strain Hypr. We also investigated changes in cytokine/chemokine production in naïve HBCA cells treated with virus-free supernatants from TBEV-infected SK-N-SH cells and in naïve SK-N-SH cells treated with virus-free supernatants from TBEV-infected HBCA cells. Additionally, a plaque assay was performed to assess how cytokine/chemokine treatment influenced viral growth following TBEV infection. RESULTS: TBEV-infected mice exhibited time-dependent increases in serum and brain tissue concentrations of multiple cytokines/chemokines (mainly CXCL10/IP-10, and also CXCL1, G-CSF, IL-6, and others). TBEV-infected SK-N-SH cells exhibited increased production of IL-8 and RANTES and downregulated MCP-1 and HGF. TBEV infection of HBCA cells activated production of a broad spectrum of pro-inflammatory cytokines, chemokines, and growth factors (mainly IL-6, IL-8, CXCL10, RANTES, and G-CSF) and downregulated the expression of VEGF. Treatment of SK-N-SH with supernatants from infected HBCA induced expression of a variety of chemokines and pro-inflammatory cytokines, reduced SK-N-SH mortality after TBEV infection, and decreased virus growth in these cells. Treatment of HBCA with supernatants from infected SK-N-SH had little effect on cytokine/chemokine/growth factor expression but reduced TBEV growth in these cells after infection. CONCLUSIONS: Our results indicated that both neurons and astrocytes are potential sources of pro-inflammatory cytokines in TBEV-infected brain tissue. Infected/activated astrocytes produce cytokines/chemokines that stimulate the innate neuronal immune response, limiting virus replication, and increasing survival of infected neurons.

• MeSH
• cytokiny imunologie   metabolismus   MeSH
• klíšťová encefalitida imunologie   metabolismus   MeSH
• lidé MeSH
• mozek imunologie   metabolismus   patologie   MeSH
• myši MeSH
• neurony imunologie   metabolismus   virologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH