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Parkinson’s disease (PD) is a neurodegenerative disease linked with the loss of dopaminer-gic neurons in the brain region called substantia nigra and caused by unknown pathogenic mecha-nisms. Two currently recognized prominent features of PD are an inflammatory response manifested by glial reaction and T-cell infiltration, as well as the presence of various toxic mediators derived from activated glial cells. PD or parkinsonism has been described after infection with several different viruses and it has therefore been hypothesized that a viral infection might play a role in the pathogen-esis of the disease. We investigated formalin-fixed post-mortem brain tissue from 9 patients with Parkinson’s disease and 11 controls for the presence of Ljungan virus (LV) antigen using a polyclonal antibody against the capsid protein of this recently identified picornavirus with neurotropic proper-ties, suspected of being both a human and an animal pathogen. Evidence of viral antigen was found in 7 out of 9 Parkinson’s disease cases and in only 1 out of 11 controls (p = 0.005). The picornavirus antigen was present in dopamine-containing neurons of the substantia nigra. We propose that LV or an LV-related virus initiates the pathological process underlying sporadic PD. LV-related picornavirus antigen has also been reported in patients with Alzheimer’s disease. Potentially successful antiviral treatment in Alzheimer’s disease suggests a similar treatment for Parkinson's disease. Amanta-dine, originally developed as an antiviral drug against influenza infection, has also been used for symptomatic treatment of patients with PD for more than 50 years and is still commonly used by neurologists today. The fact that amantadine also has an antiviral effect on picornaviruses opens the question of this drug being re-evaluated as potential PD therapy in combination with other antiviral compounds directed against picornaviruses.

Background: TBE vaccination failures among those past middle age have raised concern about immune response declining with age. We investigated immunogenicity of the TBE-vaccine FSME-Immun among those aged 50+ years using the standard three-dose primary series and alternative four-dose schedules. Methods: In this single-centre, open-label, randomized controlled trial, 200 TBE-naive Swedish adults were given primary TBE vaccination with FSME-Immun. Those aged 50+ years (n = 150) were randomized to receive the standard three-dose (days 0-30-360) or one of two four-dose series (0-7-21-360; 0-30- 90-360). For participants < 50 years (n = 50) the standard three-dose schedule was used. Titres of neu-tralizing antibodies were determined on days 0, 60, 120, 360, and 400. The main outcome was the log titre of TBE virus-specific neutralizing antibodies on day 400. Results: The three-dose schedule yielded lower antibody titres among those aged 50+ years than the younger participants on day 400 (geometric mean titre 41 versus 74, p < 0.05). The older group showed higher titres for the four-dose 0-7-21-360 than the standard three-dose schedule both on day 400 (103 versus 41, p < 0.01; primary end point) and at the other testing points (days 60,120, 360). Using the other four-dose schedule (0-30-90-360), no such difference was observed on day 400 (63 versus 41, NS). Conclusion: Immune response to the TBE vaccine declined with age. A four-dose schedule (0-7-21-360) may benefit those aged 50 years or older. This study is registered at ClinicalTrials.gov, NCT01361776. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Background: TBE vaccination failures among those past middle age have raised concern about immune response declining with age. We investigated immunogenicity of the TBE-vaccine FSME-Immun among those aged 50+ years using the standard three-dose primary series and alternative four-dose schedules. Methods: In this single-centre, open-label, randomized controlled trial, 200 TBE-naive Swedish adults were given primary TBE vaccination with FSME-Immun. Those aged 50+ years (n = 150) were randomized to receive the standard three-dose (days 0-30-360) or one of two four-dose series (0-7-21-360; 0-30- 90-360). For participants < 50 years (n = 50) the standard three-dose schedule was used. Titres of neu-tralizing antibodies were determined on days 0, 60, 120, 360, and 400. The main outcome was the log titre of TBE virus-specific neutralizing antibodies on day 400. Results: The three-dose schedule yielded lower antibody titres among those aged 50+ years than the younger participants on day 400 (geometric mean titre 41 versus 74, p < 0.05). The older group showed higher titres for the four-dose 0-7-21-360 than the standard three-dose schedule both on day 400 (103 versus 41, p < 0.01; primary end point) and at the other testing points (days 60,120, 360). Using the other four-dose schedule (0-30-90-360), no such difference was observed on day 400 (63 versus 41, NS). Conclusion: Immune response to the TBE vaccine declined with age. A four-dose schedule (0-7-21-360) may benefit those aged 50 years or older. This study is registered at ClinicalTrials.gov, NCT01361776. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Background: TBE vaccination failures among those past middle age have raised concern about immune response declining with age. We investigated immunogenicity of the TBE-vaccine FSME-Immun among those aged 50+ years using the standard three-dose primary series and alternative four-dose schedules. Methods: In this single-centre, open-label, randomized controlled trial, 200 TBE-naive Swedish adults were given primary TBE vaccination with FSME-Immun. Those aged 50+ years (n = 150) were randomized to receive the standard three-dose (days 0-30-360) or one of two four-dose series (0-7-21-360; 0-30- 90-360). For participants < 50 years (n = 50) the standard three-dose schedule was used. Titres of neu-tralizing antibodies were determined on days 0, 60, 120, 360, and 400. The main outcome was the log titre of TBE virus-specific neutralizing antibodies on day 400. Results: The three-dose schedule yielded lower antibody titres among those aged 50+ years than the younger participants on day 400 (geometric mean titre 41 versus 74, p < 0.05). The older group showed higher titres for the four-dose 0-7-21-360 than the standard three-dose schedule both on day 400 (103 versus 41, p < 0.01; primary end point) and at the other testing points (days 60,120, 360). Using the other four-dose schedule (0-30-90-360), no such difference was observed on day 400 (63 versus 41, NS). Conclusion: Immune response to the TBE vaccine declined with age. A four-dose schedule (0-7-21-360) may benefit those aged 50 years or older. This study is registered at ClinicalTrials.gov, NCT01361776. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Background: TBE vaccination failures among those past middle age have raised concern about immune response declining with age. We investigated immunogenicity of the TBE-vaccine FSME-Immun among those aged 50+ years using the standard three-dose primary series and alternative four-dose schedules. Methods: In this single-centre, open-label, randomized controlled trial, 200 TBE-naive Swedish adults were given primary TBE vaccination with FSME-Immun. Those aged 50+ years (n = 150) were randomized to receive the standard three-dose (days 0-30-360) or one of two four-dose series (0-7-21-360; 0-30- 90-360). For participants < 50 years (n = 50) the standard three-dose schedule was used. Titres of neu-tralizing antibodies were determined on days 0, 60, 120, 360, and 400. The main outcome was the log titre of TBE virus-specific neutralizing antibodies on day 400. Results: The three-dose schedule yielded lower antibody titres among those aged 50+ years than the younger participants on day 400 (geometric mean titre 41 versus 74, p < 0.05). The older group showed higher titres for the four-dose 0-7-21-360 than the standard three-dose schedule both on day 400 (103 versus 41, p < 0.01; primary end point) and at the other testing points (days 60,120, 360). Using the other four-dose schedule (0-30-90-360), no such difference was observed on day 400 (63 versus 41, NS). Conclusion: Immune response to the TBE vaccine declined with age. A four-dose schedule (0-7-21-360) may benefit those aged 50 years or older. This study is registered at ClinicalTrials.gov, NCT01361776. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

There has been an increase in reported TBE cases in Europe since 2015, reaching a peak in some countries in 2020, highlighting the need for better management of TBE risk in Europe. TBE surveillance is currently limited, in part, due to varying diagnostic guidelines, access to testing, and awareness of TBE. Consequently, TBE prevalence is underestimated and vaccination recommendations inadequate. TBE vaccine uptake is unsatisfactory in many TBE-endemic European countries. This review summarizes the findings of a scientific workshop of experts to improve TBE surveillance and vaccine uptake in Europe. Strategies to improve TBE surveillance and vaccine uptake should focus on: aligning diagnostic criteria and testing across Europe; expanding current vaccine recommendations and reducing their complexity; and increasing public education of the potential risks posed by TBEV infection.

Parkinson’s disease (PD) is a neurodegenerative disease linked with the loss of dopaminer-gic neurons in the brain region called substantia nigra and caused by unknown pathogenic mecha-nisms. Two currently recognized prominent features of PD are an inflammatory response manifested by glial reaction and T-cell infiltration, as well as the presence of various toxic mediators derived from activated glial cells. PD or parkinsonism has been described after infection with several different viruses and it has therefore been hypothesized that a viral infection might play a role in the pathogen-esis of the disease. We investigated formalin-fixed post-mortem brain tissue from 9 patients with Parkinson’s disease and 11 controls for the presence of Ljungan virus (LV) antigen using a polyclonal antibody against the capsid protein of this recently identified picornavirus with neurotropic proper-ties, suspected of being both a human and an animal pathogen. Evidence of viral antigen was found in 7 out of 9 Parkinson’s disease cases and in only 1 out of 11 controls (p = 0.005). The picornavirus antigen was present in dopamine-containing neurons of the substantia nigra. We propose that LV or an LV-related virus initiates the pathological process underlying sporadic PD. LV-related picornavirus antigen has also been reported in patients with Alzheimer’s disease. Potentially successful antiviral treatment in Alzheimer’s disease suggests a similar treatment for Parkinson's disease. Amanta-dine, originally developed as an antiviral drug against influenza infection, has also been used for symptomatic treatment of patients with PD for more than 50 years and is still commonly used by neurologists today. The fact that amantadine also has an antiviral effect on picornaviruses opens the question of this drug being re-evaluated as potential PD therapy in combination with other antiviral compounds directed against picornaviruses.

There has been an increase in reported TBE cases in Europe since 2015, reaching a peak in some countries in 2020, highlighting the need for better management of TBE risk in Europe. TBE surveillance is currently limited, in part, due to varying diagnostic guidelines, access to testing, and awareness of TBE. Consequently, TBE prevalence is underestimated and vaccination recommendations inadequate. TBE vaccine uptake is unsatisfactory in many TBE-endemic European countries. This review summarizes the findings of a scientific workshop of experts to improve TBE surveillance and vaccine uptake in Europe. Strategies to improve TBE surveillance and vaccine uptake should focus on: aligning diagnostic criteria and testing across Europe; expanding current vaccine recommendations and reducing their complexity; and increasing public education of the potential risks posed by TBEV infection.

Background: TBE vaccination failures among those past middle age have raised concern about immune response declining with age. We investigated immunogenicity of the TBE-vaccine FSME-Immun among those aged 50+ years using the standard three-dose primary series and alternative four-dose schedules. Methods: In this single-centre, open-label, randomized controlled trial, 200 TBE-naive Swedish adults were given primary TBE vaccination with FSME-Immun. Those aged 50+ years (n = 150) were randomized to receive the standard three-dose (days 0-30-360) or one of two four-dose series (0-7-21-360; 0-30- 90-360). For participants < 50 years (n = 50) the standard three-dose schedule was used. Titres of neu-tralizing antibodies were determined on days 0, 60, 120, 360, and 400. The main outcome was the log titre of TBE virus-specific neutralizing antibodies on day 400. Results: The three-dose schedule yielded lower antibody titres among those aged 50+ years than the younger participants on day 400 (geometric mean titre 41 versus 74, p < 0.05). The older group showed higher titres for the four-dose 0-7-21-360 than the standard three-dose schedule both on day 400 (103 versus 41, p < 0.01; primary end point) and at the other testing points (days 60,120, 360). Using the other four-dose schedule (0-30-90-360), no such difference was observed on day 400 (63 versus 41, NS). Conclusion: Immune response to the TBE vaccine declined with age. A four-dose schedule (0-7-21-360) may benefit those aged 50 years or older. This study is registered at ClinicalTrials.gov, NCT01361776. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Tick-borne encephalitis (TBE) is a viral infection of the CNS caused by TBE virus. With no specific treatment available, the only protection is a formalin-inactivated whole virus vaccine. Primary immunization with European TBE vaccines, as recommended by the manufacturers, consists of three vaccine doses administered within a 1-y period. Protection from vaccination is believed to be mediated by Abs, yet T cells may also have a protective role. We set out to characterize the human CD4(+) T cell response throughout primary TBE immunization. The responses were evaluated before vaccination and 1 mo after each vaccine dose. A heterogeneous magnitude of CD4(+) T cell-mediated memory responses was observed in regard to lymphoblast expansion and cytokine production (IFN-gamma, IL-2, and TNF), with the highest median magnitude detected after the second dose of vaccine. Stimulation with an overlapping peptide library based on structural TBE virus proteins E and C revealed that CD4(+) T cells concomitantly producing IL-2 and TNF dominated the responses from vaccinees after each vaccine dose, whereas a control cohort of TBE patients responded mainly with all three cytokines. CD107a expression was not upregulated upon peptide stimulation in the vaccinees. However, CD154 (CD40L) expression on cytokine-positive memory CD4(+) T cells significantly increased after the second vaccine dose. Taken together, TBE vaccination induced CD4(+) T cell responses dominated by IL-2 and TNF production together with CD154 upregulation and a lower IFN-gamma response compared with TBE patients. This response pattern was consistent after all three doses of TBE vaccine.

BACKGROUND: Southern Sweden is endemic for tick borne encephalitis (TBE), with Stockholm County as one of the high-risk areas. The aim of this study was to describe cases of vaccine failures, and to optimize future vaccination recommendations. METHODS: Patients with TBE were identified in the notification database at the Department of Communicable Disease Control and Prevention in the county of Stockholm during 2006-2015. Vaccine failure was defined as TBE despite adherence to the recommended vaccination schedule with at least two doses. Clinical data were extracted from medical records. RESULTS: A total of 1004 TBE cases were identified, 53 (5%) were defined as vaccine failures. In this latter group the median age was 62 years (6-83). Forty-three (81%) patients were over 50 years of age and two were children. Approximately half of the patients had comorbidities with diseases affecting the immune system accounting for 26% of all cases.Vaccine failures following the third or fourth vaccine dose accounted for 36 (68%) of the patients. Severe and moderate TBE disease affected 81% of the cases. CONCLUSION: To our knowledge, this is the largest documented cohort of TBE-vaccine failures. Vaccine failure after five TBE-vaccine doses is rare. Our data provides rationale for adding an extra priming dose to the age group 50 years and older., Funding Agencies:Research Committee of Orebro lan OLL-768871Hennes Kungliga Höghet Kronprinsessan Lovisas förening for barnasjukvård/Stiftelsen Axel Tielmans Minnesfond

Background. In suspected acute bacterial meningitis (ABM), cerebral computerized tomography (CT) is recommended before lumbar puncture (LP) if mental impairment. Despite guideline emphasis on early treatment, performing CT prior to LP implies a risk of delayed treatment and unfavorable outcome. Therefore, Swedish guidelines were revised in 2009, deleting impaired mental status as a contraindication for LP without prior CT scan. The aim of the present study was to evaluate the guideline revision. Methods. The Swedish quality registry for community-acquired ABM was analyzed retrospectively. Door-to-antibiotic time and outcome were compared among patients treated 2005-2009 (n = 394) and 2010-2012 (n = 318). The effect of different LP-CT sequences was analyzed during 2008-2012. Results. Adequate treatment was started 1.2 hours earlier, and significantly more patients were treated <2 hours from admission 2010-2012 than 2005-2009. Compared with CT before LP, immediate LP resulted in 1.6 hours earlier treatment, significant increase in door-to-antibiotic times of <1 and <2 hours, and a favorable outcome. In 2010-2012, mortality was lower (6.9% vs 11.7%) and the risk of sequelae at follow-up decreased (38% vs 49%) in comparison with 2005-2009. Treatment delay resulted in a significantly increased risk for fatal outcome, with a relative increase in mortality of 12.6% per hour of delay. Conclusions. The deletion of impaired mental status as contraindication for prompt LP and LP without prior CT scan are associated with significantly earlier treatment and a favorable outcome. A revision of current international guidelines should be considered.

Background: Tick-borne encephalitis virus (TBEV) infections can be asymptomatic or cause moderate to severe injuries of the nervous system. We previously reported that a nonfunctional chemokine receptor 5 (CCR5) and a functional Toll-like receptor 3 (TLR3) predispose adults to clinical tick-borne encephalitis (TBE). This study expands our previous findings and further examines polymorphisms in CCR5 and TLR3 genes in different age and disease severity groups. Methods: 117 children and 129 adults, stratified into mild, moderate and severe forms of TBE, and 103 adults with severe TBE were analyzed. 135 healthy individuals and 79 patients with aseptic meningoencephalitis served as controls. CCR5 delta 32 and rs3775291 TLR3 genotypes were established by pyrosequencing, and their frequencies were analyzed using recessive genetic, genotype and allelic models. Findings: The prevalence of CCR5 Delta 32 homozygotes was higher in children (2.5%), in adults with severe TBE (1.9%), and in the combined cohort of TBE patients (2.3%) than in controls (0%) (pless than0.05). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p = 0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. However, in the severe adult TBE cohort, homozygous functional TLR3 genotype and wt allele were less prevalent compared to the adult cohort with the whole disease severity spectrum (44.4% vs 59.8% p = 0.022 and 65.2% vs 76.4% p = 0.009; respectively). Conclusions: Independently of age, nonfunctional CCR5D32 mutation is a significant risk factor for development of clinical TBE, but not for disease severity. The polymorphism of TLR3 gene predisposes to clinical TBE in adults only and may be associated with disease severity. Further studies are needed to clarify the role of these polymorphisms, Funding Agencies|Research Council of Lithuania [MIP-11174]; Swedish Research Council [3485]

Background: Tick-borne encephalitis virus (TBEV) infections can be asymptomatic or cause moderate to severe injuries of the nervous system. We previously reported that a nonfunctional chemokine receptor 5 (CCR5) and a functional Toll-like receptor 3 (TLR3) predispose adults to clinical tick-borne encephalitis (TBE). This study expands our previous findings and further examines polymorphisms in CCR5 and TLR3 genes in different age and disease severity groups. Methods: 117 children and 129 adults, stratified into mild, moderate and severe forms of TBE, and 103 adults with severe TBE were analyzed. 135 healthy individuals and 79 patients with aseptic meningoencephalitis served as controls. CCR5 delta 32 and rs3775291 TLR3 genotypes were established by pyrosequencing, and their frequencies were analyzed using recessive genetic, genotype and allelic models. Findings: The prevalence of CCR5 Delta 32 homozygotes was higher in children (2.5%), in adults with severe TBE (1.9%), and in the combined cohort of TBE patients (2.3%) than in controls (0%) (pless than0.05). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p = 0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. However, in the severe adult TBE cohort, homozygous functional TLR3 genotype and wt allele were less prevalent compared to the adult cohort with the whole disease severity spectrum (44.4% vs 59.8% p = 0.022 and 65.2% vs 76.4% p = 0.009; respectively). Conclusions: Independently of age, nonfunctional CCR5D32 mutation is a significant risk factor for development of clinical TBE, but not for disease severity. The polymorphism of TLR3 gene predisposes to clinical TBE in adults only and may be associated with disease severity. Further studies are needed to clarify the role of these polymorphisms, Funding Agencies|Research Council of Lithuania [MIP-11174]; Swedish Research Council [3485]

Erkinis encefalitas (EE) – pati dažniausia ir sunkiausia virusinė nervų sistemos infekcija Lietuvoje, kuria per metus vidutiniškai suserga 400 žmonių. Užsikrėtus EE virusu (EEV), galima besimptomė arba klinikinius požymius sukelianti ligos eiga, turinti platų požymių spektrą – nuo lengvos, meningitinės ligos formos iki sunkaus encefalito. Nors mirštamumas nuo EE yra nedidelis, svarbiausia problema – ilgai trunkantis sveikimo laikotarpis ir ilgalaikiai liekamieji reiškiniai, kurie būdingi 26–46 proc. persirgusiųjų. Neaišku, kodėl užsikrėtę identiško virulentiškumo virusu, vieni žmonės perserga besimptome arba lengva EE forma, o kitiems atsiranda sunkus nervų sistemos pažeidimas. Manoma, kad didelę reikšmę turi žmogaus genetiniai veiksniai. Nesant specifinio priešvirusinio EE gydymo, šios sunkios centrinės nervų sistemos infekcijos patogenezės ir genetinių rizikos veiksnių tyrimai yra ypač svarbūs, siekiant nustatyti galimas veiksmingo gydymo paieškos kryptis ateityje. Šio darbo tikslas – nustatyti CCR5 ir TLR3 genų polimorfizmų paplitimą tarp EE sirgusių asmenų ir šių genų polimorfizmų reikšmę polinkiui sirgti EE bei skirtingoms EE klinikinėms formoms išsivystyti. Šis darbas yra didžiausias iki šiol atliktas genetinių veiksnių reikšmės EEV infekcijos metu tyrimas ir pirmasis tokio pobūdžio vaikų tyrimas. Tyrimo rezultatai patvirtino hipotezę, kad nefunkcionuojantis CCR5 ir funkcionuojantis TLR3 yra reikšmingi simptominės EE formos išsivystymo veiksniai, užsikrėtus EEV., Tick-borne encephalitis (TBE) is the most common and severe viral infection of the central nervous system in Lithuania, with the average number of 400 cases per year. The clinical spectrum of TBE virus infection varies considerably from asymptomatic to mild meningitis or severe encephalitis. Although the mortality of TBE is relatively low, as many as 26–46% of the patients experience long-lasting sequelae. No specific treatment for TBE exists. A most intriguing question is why certain individuals respond with seve¬re clinical symptoms after infection with TBEV while the majority either remains asymptomatic or develops only mild disease. Studies of host genetic susceptibility to infectious diseases aim to in¬crea¬se our understanding of why some individuals are more susceptable than others. Knowledge of genetic susceptibility may be used in develope¬ment of new therapeutic means and also to recognize individuals who are at increased risk of severe symptoms if infected with a pathogen. The aim of this study – to establish the prevalence of the polymorphisms in CCR5 and TLR3 genes in TBE patients and their role in susceptibility to clinical TBE and disease severity. This study is the largest study on the host genetic risk factors predis¬posing to TBEV infection, and the first study of such kind performed in the pediatric population. The results of this study confirmed that a non¬func¬tional CCR5 protein and a functional TLR3 receptor are associated with the clinical expression... [to full text]

Erkinis encefalitas (EE) – pati dažniausia ir sunkiausia virusinė nervų sistemos infekcija Lietuvoje, kuria per metus vidutiniškai suserga 400 žmonių. Užsikrėtus EE virusu (EEV), galima besimptomė arba klinikinius požymius sukelianti ligos eiga, turinti platų požymių spektrą – nuo lengvos, meningitinės ligos formos iki sunkaus encefalito. Nors mirštamumas nuo EE yra nedidelis, svarbiausia problema – ilgai trunkantis sveikimo laikotarpis ir ilgalaikiai liekamieji reiškiniai, kurie būdingi 26–46 proc. persirgusiųjų. Neaišku, kodėl užsikrėtę identiško virulentiškumo virusu, vieni žmonės perserga besimptome arba lengva EE forma, o kitiems atsiranda sunkus nervų sistemos pažeidimas. Manoma, kad didelę reikšmę turi žmogaus genetiniai veiksniai. Nesant specifinio priešvirusinio EE gydymo, šios sunkios centrinės nervų sistemos infekcijos patogenezės ir genetinių rizikos veiksnių tyrimai yra ypač svarbūs, siekiant nustatyti galimas veiksmingo gydymo paieškos kryptis ateityje. Šio darbo tikslas – nustatyti CCR5 ir TLR3 genų polimorfizmų paplitimą tarp EE sirgusių asmenų ir šių genų polimorfizmų reikšmę polinkiui sirgti EE bei skirtingoms EE klinikinėms formoms išsivystyti. Šis darbas yra didžiausias iki šiol atliktas genetinių veiksnių reikšmės EEV infekcijos metu tyrimas ir pirmasis tokio pobūdžio vaikų tyrimas. Tyrimo rezultatai patvirtino hipotezę, kad nefunkcionuojantis CCR5 ir funkcionuojantis TLR3 yra reikšmingi simptominės EE formos išsivystymo veiksniai, užsikrėtus EEV., Tick-borne encephalitis (TBE) is the most common and severe viral infection of the central nervous system in Lithuania, with the average number of 400 cases per year. The clinical spectrum of TBE virus infection varies considerably from asymptomatic to mild meningitis or severe encephalitis. Although the mortality of TBE is relatively low, as many as 26–46% of the patients experience long-lasting sequelae. No specific treatment for TBE exists. A most intriguing question is why certain individuals respond with seve¬re clinical symptoms after infection with TBEV while the majority either remains asymptomatic or develops only mild disease. Studies of host genetic susceptibility to infectious diseases aim to in¬crea¬se our understanding of why some individuals are more susceptable than others. Knowledge of genetic susceptibility may be used in develope¬ment of new therapeutic means and also to recognize individuals who are at increased risk of severe symptoms if infected with a pathogen. The aim of this study – to establish the prevalence of the polymorphisms in CCR5 and TLR3 genes in TBE patients and their role in susceptibility to clinical TBE and disease severity. This study is the largest study on the host genetic risk factors predis¬posing to TBEV infection, and the first study of such kind performed in the pediatric population. The results of this study confirmed that a non¬func¬tional CCR5 protein and a functional TLR3 receptor are associated with the clinical expression... [to full text]

Background: Tick-borne encephalitis virus (TBEV) infections can be asymptomatic or cause moderate to severe injuries of the nervous system. We previously reported that a nonfunctional chemokine receptor 5 (CCR5) and a functional Toll-like receptor 3 (TLR3) predispose adults to clinical tick-borne encephalitis (TBE). This study expands our previous findings and further examines polymorphisms in CCR5 and TLR3 genes in different age and disease severity groups. Methods: 117 children and 129 adults, stratified into mild, moderate and severe forms of TBE, and 103 adults with severe TBE were analyzed. 135 healthy individuals and 79 patients with aseptic meningoencephalitis served as controls. CCR5 delta 32 and rs3775291 TLR3 genotypes were established by pyrosequencing, and their frequencies were analyzed using recessive genetic, genotype and allelic models. Findings: The prevalence of CCR5 Delta 32 homozygotes was higher in children (2.5%), in adults with severe TBE (1.9%), and in the combined cohort of TBE patients (2.3%) than in controls (0%) (pless than0.05). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p = 0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. However, in the severe adult TBE cohort, homozygous functional TLR3 genotype and wt allele were less prevalent compared to the adult cohort with the whole disease severity spectrum (44.4% vs 59.8% p = 0.022 and 65.2% vs 76.4% p = 0.009; respectively). Conclusions: Independently of age, nonfunctional CCR5D32 mutation is a significant risk factor for development of clinical TBE, but not for disease severity. The polymorphism of TLR3 gene predisposes to clinical TBE in adults only and may be associated with disease severity. Further studies are needed to clarify the role of these polymorphisms, Funding Agencies|Research Council of Lithuania [MIP-11174]; Swedish Research Council [3485]

Objective: To assess the presence of two major non-nucleoside reverse transcriptase inhibitors (NNRTI) drug resistance mutations (DRMs), Y181C and K103N, in minor viral quasispecies of treatment naive HIV-1 infected East-African and Swedish patients by allele-specific polymerase chain reaction (AS-PCR). Methods: Treatment naive adults (n = 191) with three epidemiological backgrounds were included: 92 Ethiopians living in Ethiopia; 55 East-Africans who had migrated to Sweden; and 44 Caucasians living in Sweden. The pol gene was analysed by standard population sequencing and by AS-PCR for the detection of Y181C and K103N. Results: The Y181C was detected in the minority quasispecies of six Ethiopians (6.5%), in two Caucasians (4.5%), and in one East-African (1.8%). The K103N was detected in one East-African (1.8%), by both methods. The proportion of mutants ranged from 0.25% to 17.5%. Additional DRMs were found in all three treatment naive patient groups by population sequencing. Conclusions: Major NNRTI mutations can be found by AS-PCR in minor quasispecies of treatment naive HIV-1 infected Ethiopians living in Ethiopia, in East-African and Caucasian patients living in Sweden in whom population sequencing reveal wild-type virus only. Surveys with standard sequencing are likely to underestimate transmitted drug resistance and the presence of resistant minor quasispecies in treatment naive patients should be topic for future large scale studies., Funding Agencies:European and Developing Countries Clinical Trial PartnershipSwedish Civil Contingencies Agency7th Framework Programme of European Union, Collaborative HIV and Anti-HIV Drug Resistance Network

INTRODUCTION: The role of microbial translocation (MT) in HIV patients living with HIV from low- and middle-income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden. METHODS: Cross-sectional samples were obtained from treatment-naïve patients living with HIV-1 and healthy controls from Vietnam (n=83; n=46), Ethiopia (n=9492; n=50) and Sweden (n=51; n=19). Longitudinal samples were obtained from a subset of the Vietnamese (n=24) in whom antiretroviral therapy (ART) and tuberculostatics were given. Plasma lipopolysaccharide (LPS), sCD14 and anti-flagellin IgG were determined by the endpoint chromogenic Limulus Amebocyte Assay and enzyme-linked immunosorbent assay. RESULTS: All three biomarkers were significantly increased in patients living with HIV-1 from all countries as compared to controls. No differences were found between males and females. Vietnamese and Ethiopian patients had significantly higher levels of anti-flagellin IgG and LPS, as compared to Swedes. ART reduced these levels for the Vietnamese. Vietnamese patients given tuberculostatics at initiation of ART had significantly lower levels of anti-flagellin IgG and higher sCD14. The biomarkers were lower in Vietnamese who did not develop opportunistic infection. CONCLUSIONS: Higher MT is common in patients living with HIV compared to healthy individuals, and in patients from LMICs compared to patients from a high-income country. Treatment with tuberculostatics decreased MT while higher levels of MT are associated with a poorer clinical outcome., Funding Agencies:European and Developing Countries Clinical Trial PartnershipSwedish Civil Contingencies Agency SWE-2009-151

Background: Tick-borne encephalitis virus (TBEV) infections can be asymptomatic or cause moderate to severe injuries of the nervous system. We previously reported that a nonfunctional chemokine receptor 5 (CCR5) and a functional Toll-like receptor 3 (TLR3) predispose adults to clinical tick-borne encephalitis (TBE). This study expands our previous findings and further examines polymorphisms in CCR5 and TLR3 genes in different age and disease severity groups. Methods: 117 children and 129 adults, stratified into mild, moderate and severe forms of TBE, and 103 adults with severe TBE were analyzed. 135 healthy individuals and 79 patients with aseptic meningoencephalitis served as controls. CCR5 delta 32 and rs3775291 TLR3 genotypes were established by pyrosequencing, and their frequencies were analyzed using recessive genetic, genotype and allelic models. Findings: The prevalence of CCR5 Delta 32 homozygotes was higher in children (2.5%), in adults with severe TBE (1.9%), and in the combined cohort of TBE patients (2.3%) than in controls (0%) (pless than0.05). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p = 0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. However, in the severe adult TBE cohort, homozygous functional TLR3 genotype and wt allele were less prevalent compared to the adult cohort with the whole disease severity spectrum (44.4% vs 59.8% p = 0.022 and 65.2% vs 76.4% p = 0.009; respectively). Conclusions: Independently of age, nonfunctional CCR5D32 mutation is a significant risk factor for development of clinical TBE, but not for disease severity. The polymorphism of TLR3 gene predisposes to clinical TBE in adults only and may be associated with disease severity. Further studies are needed to clarify the role of these polymorphisms, Funding Agencies|Research Council of Lithuania [MIP-11174]; Swedish Research Council [3485]

BACKGROUND & AIMS: There is a demand for more sensitive, specific and predictive biomarkers for drug-induced liver injury (DILI) than the gold standard used today, alanine aminotransferase (ALT). The aim of this study was to qualify novel DILI biomarkers (keratin-18 markers M65/M30, microRNA-122, glutamate dehydrogenase and alpha-foetoprotein) in human DILI. METHODS: Levels of the novel biomarkers were measured by enzyme-linked immunosorbent assay or real-time quantitative reverse-transcription PCR (qRT-PCR) in two human DILI cohorts: a human volunteer study with acetaminophen and a human immunodeficiency virus (HIV)/tuberculosis (TB) study. RESULTS: In the acetaminophen study, serum M65 and microRNA-122 levels were significantly increased at an earlier time point than ALT. Furthermore, the maximal elevation of M65 and microRNA-122 exceeded the increase in ALT. In the HIV/TB study, all the analysed novel biomarkers increased after 1 week of treatment. In contrast to ALT, the novel biomarkers remained stable in a human cohort with exercise-induced muscular injury. CONCLUSIONS: M65 and microRNA-122 are potential biomarkers of DILI superior to ALT with respect to sensitivity and specificity.

Background: Tick-borne encephalitis virus (TBEV) infections can be asymptomatic or cause moderate to severe injuries of the nervous system. We previously reported that a nonfunctional chemokine receptor 5 (CCR5) and a functional Toll-like receptor 3 (TLR3) predispose adults to clinical tick-borne encephalitis (TBE). This study expands our previous findings and further examines polymorphisms in CCR5 and TLR3 genes in different age and disease severity groups. Methods: 117 children and 129 adults, stratified into mild, moderate and severe forms of TBE, and 103 adults with severe TBE were analyzed. 135 healthy individuals and 79 patients with aseptic meningoencephalitis served as controls. CCR5 delta 32 and rs3775291 TLR3 genotypes were established by pyrosequencing, and their frequencies were analyzed using recessive genetic, genotype and allelic models. Findings: The prevalence of CCR5 Delta 32 homozygotes was higher in children (2.5%), in adults with severe TBE (1.9%), and in the combined cohort of TBE patients (2.3%) than in controls (0%) (pless than0.05). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p = 0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. However, in the severe adult TBE cohort, homozygous functional TLR3 genotype and wt allele were less prevalent compared to the adult cohort with the whole disease severity spectrum (44.4% vs 59.8% p = 0.022 and 65.2% vs 76.4% p = 0.009; respectively). Conclusions: Independently of age, nonfunctional CCR5D32 mutation is a significant risk factor for development of clinical TBE, but not for disease severity. The polymorphism of TLR3 gene predisposes to clinical TBE in adults only and may be associated with disease severity. Further studies are needed to clarify the role of these polymorphisms, Funding Agencies|Research Council of Lithuania [MIP-11174]; Swedish Research Council [3485]

Patients with viral infections of the central nervous system (CNS) may present with a variety of neurological symptoms, most commonly dominated by either encephalitis or meningitis. The aetiological panorama varies in different parts of the world as well as over time. Thus, virological first-line diagnostics must be adapted to the current epidemiological situation and to the individual patient history, including recent travels. This review focuses on the diagnostics and treatment of viral CNS infections in the immunocompetent host from a Northern European perspective. Effective vaccines are available for viruses such as poliovirus and tick-borne encephalitis virus (TBEV) and for the childhood diseases morbilli (measles), rubella (German measles), parotitis (mumps) and varicella (chickenpox). However, cases do appear due to suboptimal immunization rates. In viral CNS infections, epidemiological surveillance is essential for establishing preventive strategies and for detecting emerging viruses. Knowledge of the possibilities and limitations of diagnostic methods for specific viral CNS infections is vital. A positive cerebral spinal fluid (CSF) polymerase chain reaction (PCR) finding is usually reliable for aetiological diagnosis. The demonstration of intrathecal antibody synthesis is useful for confirming the aetiology in a later stage of disease, hitherto sufficiently evaluated in herpes simplex encephalitis (HSE) and tick-borne encephalitis (TBE). Despite improved virological and differential diagnostic methods, aetiology remains unknown in about half of the cases with suspected viral encephalitis. Antiviral treatment is available chiefly for infections caused by herpesviruses, and acyclovir (aciclovir) is the drug of choice for empirical therapy in suspected viral encephalitis. However, randomized, controlled antiviral trials have only been conducted for HSE, while such studies are lacking in other viral CNS infections. Viral cytolysis and immune-mediated mechanism

Current international guidelines recommend cerebral computerized tomography (CT) before lumbar puncture (LP) in many adults with suspected acute bacterial meningitis (ABM), due to concern about LP-induced cerebral herniation. Despite guideline emphasis on early treatment based on symptoms, performing CT prior to LP implies a risk of delayed ABM treatment, which may be associated with a fatal outcome. Firm evidence for LP-induced herniation in adult ABM is absent and brain CT cannot discard herniation. Thus, the recommendation to perform CT before LP may contribute to an avoidable delay of LP and ABM treatment. The inappropriate use of the diagnostic treatment sequence of brain CT scan, followed by LP, followed by antibiotics and corticosteroids should be avoided in adults with suspected ABM by omitting needless contraindications for LP, thus eliminating an unnecessary fear of immediate LP. Revised Swedish guidelines regarding early LP are presented, and the background documentation and reasons for omitting impaired consciousness, new onset seizures, and immunocompromised state as contraindications to LP are discussed.

Background: The inactivated Vero cell-derived vaccine (JE-VC, IXIARO) has replaced the traditional mouse brain-derived preparations (JE-MB) in travelers' vaccinations against Japanese encephalitis. We showed recently that a single JE-VC dose efficiently boosts immunity in JE-MB-primed vaccinees, and that JE-VC elicits cross-protective immunity against non-vaccine genotypes, including the emerging genotype I. While these studies only provided short-term data, the present investigation evaluates the longevity of seroprotection in the same volunteers. Methods: The study comprised 48 travelers who had received (1) JE-VC primary series, (2) JE-MB primary series followed by a single JE-VC booster dose, or (3) JE-MB primary series and a single JE-MB booster dose. Serum samples were collected two years after the last vaccine dose, and evaluated with the plaque-reduction neutralization test against seven Japanese encephalitis virus strains representing genotypes I-IV. PRNT50 titers >= 10 were considered protective. Results: Two years after the primary series with JE-VC, 87-93% of the vaccinees proved to be cross-protected against test strains representing genotypes II-IV and 73% against those of genotype I. After a single homologous or heterologous booster dose to JE-MB-primed subjects, the two-year seroprotection rates against genotype I-IV strains were 89-100%. Conclusions: After JE-VC primary series, seroprotection appeared to wane first against genotype I. The first booster should not be delayed beyond two years. In JE-MB-primed subjects, a single JE-VC booster provided cross-protective immunity against genotype I-IV strains in almost all vaccinees, suggesting an interval of two years or even longer for the second booster. These data further support the use of a single JE-VC dose for boosting JE-MB immunity.

Current Japanese encephalitis vaccines are derived from strains of genotype III, yet heterologous genotypes are emerging in endemic areas. Inactivated vaccines given to European travelers were found to elicit protective levels of neutralizing antibodies against heterologous strains of genotypes I-IV.

BACKGROUND: A significant part of the world population lives in areas with endemic Japanese encephalitis (JE). For travelers from nonendemic countries, Vero cell-derived vaccine (JE-VC; Ixiaro) has replaced traditional mouse brain-derived vaccines (JE-MB) associated with safety concerns. The 2 vaccines are derived from different viral strains: JE-VC from the SA14-14-2 strain and JE-MB from the Nakayama strain. No data exist regarding whether JE-VC can be used to boost immunity after a primary series of JE-MB; therefore, a primary series of JE-VC has been recommended to all travelers regardless of previous vaccination history. METHODS: One hundred twenty travelers were divided into 4 groups: Volunteers with no prior JE vaccination received primary immunization with (group 1) JE-MB or (group 2) JE-VC, and those primed with JE-MB received a single booster dose of (group 3) JE-MB or (group 4) JE-VC. Immune responses were tested before and 4-8 weeks after vaccination using plaque reduction neutralization test (PRNT) against both vaccine strains. RESULTS: In vaccine-naive travelers, the vaccination response rate for test strains Nakayama and SA14-14-2 was 100% and 87% after primary vaccination with JE-MB and 87% and 94% after JE-VC, respectively. Antibody levels depended on the target virus, with higher titers against homologous than heterologous PRNT(50) target strain (P < .001). In travelers primed with JE-MB, vaccination response rates were 91% and 91%, and 98% and 95% after a booster dose of JE-MB or JE-VC, respectively. Subgroup analysis revealed that a higher proportion of primed (98%/95%) than nonprimed (39%/42%) volunteers responded to a single dose of JE-VC (P < .001). CONCLUSIONS: A single dose of JE-VC effectively boosted immunity in JE-MB-primed travelers. Current recommendations should be reevaluated. CLINICAL TRIALS REGISTRATION: NCT01386827.

Tick-borne encephalitis (TBE) is associated with higher morbidity and induces a stronger intrathecal immune activation than most other viral induced meningo-encephalitis. The aim of this study was to investigate cytokine concentrations in cerebrospinal fluid (CSF) and serum in relation to aetiology and clinical course. Cytokines were analysed by Enzyme-linked Immuno Assay (ELISA) from 44 patients with TBE and from 36 patients with aseptic meningo-encephalitis of other aetiology (non-TBE). Significantly increased CSF levels of Interferon-γ (IFN-γ), Interleukin-10 (IL-10), Interleukin-6 (IL-6), Interleukin-1 receptor antagonist (IL- 1ra), and soluble CD8 receptor (sCD8) were detected in both cohorts. Tumour necrosis factor-α (TNF-α showed low levels or was not detected in CSF in any group in the acute stage. However, the CSF levels of IL- 10 were significantly lower in TBE than in non-TBE cases 06 days after onset of encephalitis. The TBE patients with encephalitis had significantly lower IL-10 CSF levels later in the clinical course (day 718) than TBE patients with meningeal disease. Increased IFN-γ production, but low IL-10 secretion, may be of pathophysiological significance in TBE.

Background. Tick-borne encephalitis virus (TBEV) infections may be asymptomatic or cause severe symptoms in the central nervous system. A mutation in the chemokine receptor 5 gene has been associated with increased risk of TBE but explains only a limited number of cases. Investigations of further risk factors are needed. Method. To investigate the importance of the innate immune response, we analyzed 128 TBE patients, 77 patients with aseptic meningoencephalitis (AME) and 135 healthy controls, for 3mutations: 2 in the Toll-like receptor 3 (TLR3) gene and 1 in the 2-5-oligoadenylate synthetase (OAS1) gene. Results. Although no association was found between the mutation in the OAS1 gene and TBE, the genotype distribution ofrs3775291, a mutation in TLR3, differed significantly between TBE patients and controls; 61%, 32%, and 7% of the TBE patients were carriers of the wild-type, heterozygous, and mutant genotype of rs3775291, respectively. The corresponding percentages among healthy controls (n = 126) were 52%, 29%, and 19% (P = .02), and among AME patients (n = 75) were 47%, 32%, and 21% (P = .009). Additionally, the wild-type rs3775291 allele was more common among TBE patients than among healthy controls (allele frequency, .768 vs .663; P = .01). Conclusion. A functional TLR3 is a risk factor for TBEV infection.

Tick-borne encephalitis (TBE) is a major disease of the central nervous system in Europe and is endemic in Sweden with about 200 notified cases annually. The far most effective protective measure against TBE is active immunisation. The vaccines available today induce a high degree of protection in field studies. However, vaccine failures have occasionally been reported and may be overlooked due to different, and sometimes confusing, antibody kinetics in vaccinees with TBEV infection. In this study, 27 patients with clinical and serological evidences of TBE despite adequate immunisation are presented. Vaccination failure is characterized by a slow, and initially non-detectable, development of the specific TBEV-IgM response, seen together with a rapid rise of IgG and neutralising antibodies in serum. The majority (70%) of the patients were more than 50 years of age, which may implicate a need for a modified immunisation strategy in the elderly.

The ATLAS detector as installed in its experimental cavern at point 1 at CERN is described in this paper. A brief overview of the expected performance of the detector when the Large Hadron Collider begins operation is also presented., ATLAS collaboration

Tickborne encephalitis (TBE) virus infections can be asymptomatic or cause moderate to severe injuries of the central nervous system. Why some individuals develop severe disease is unknown, but a role for host genetic factors has been suggested. To investigate whether chemokine receptor CCR5 is associated with TBE, CCR5Δ32 genotyping was performed among Lithuanian patients with TBE (n = 129) or with aseptic meningoencephalitis (n = 76) as well as among control subjects (n = 134). We found individuals homozygous for CCR5Δ32 (P = .026) only among patients with TBE and a higher allele prevalence among patients with TBE compared with the other groups studied. CCR5Δ32 allele prevalence also increased with the clinical severity of disease. © 2007 by the Infectious Diseases Society of America. All rights reserved.

CNI-1493, a potent macrophage deactivator, was used to treat infant rats systemically infected with Haemophilus influenzae type b (Hib). CNI-1493 was injected 1 h prior to bacterial inoculation and 24 h later and resulted in a 75 percent increased rate of survival compared to that for untreated controls. The effect of CNI-1493 on the inflammatory response was studied by immunohistochemical detection of individual tumor necrosis factor alpha (TNF-α)-, interleukin 1 beta (IL-1β)-, and gamma interferon (IFN-γ)-producing cells in the spleen. A significant reduction of the incidence of TNF-α- and IL-1β-expressing cells was found for CNI-1493-treated animals. IFN-γ expression was not suppressed by CNI-1493, indicating that cytokine inhibition was specific in macrophages. CNI-1493 significantly reduced the number of infiltrating granulocytes in the brain from that for controls. This study provides evidence that CNI-1493 protects against lethal Hib infection by deactivating the inflammatory cascade in infant rats.

Chemokines are low-molecular-weight chemotactic cytokines that have been shown to play a central role in the perivascular transmigration and accumulation of specific subsets of leukocytes at sites of tissue damage. Using in situ hybridization (ISH), we investigated the mRNA induction of macrophage inflammatory protein 2 (MIP-2), MIP-1α, monocyte chemoattractant protein 1 (MCP-1), and RANTES. Challenge of infant rats’ brains with Haemophilus influenzae type b intraperitoneally resulted in the time-dependent expression of MIP-2, MIP-1α, MCP-1, and RANTES, which was maximal 24 to 48 h postinoculation. Immunohistochemistry showed significant increases in neutrophils and macrophages infiltrating the meninges, the ventricular system, and the periventricular area. The kinetics of MIP-2, MIP-1α, MCP-1, and RANTES mRNA expression paralleled those of the recruitment of inflammatory cells and disease severity. Administration of anti-MIP-2 or anti-MIP-1α antibodies (Abs) resulted in significant reduction of neutrophils. Administration of anti-MCP-1 Abs significantly decreased macrophage infiltration. Combined studies of ISH and immunohistochemistry showed that MIP-2- and MIP-1α-positive cells were neutrophils and macrophages. MCP-1-positive cells were neutrophils, macrophages, and astrocytes. Expression of RANTES was localized predominantly to resident astrocytes and microglia. The present study indicates that blocking of MIP-2 or MIP-1α bioactivity in vivo results in decreased neutrophil influx. These data are also the first demonstration that the C-C chemokine MIP-1α is involved in neutrophil recruitment in vivo.

Infections with tick‐borne encephalitis virus (TBEV) may be asymptomatic or cause severe symptoms from the central nervous system, such as meningitis or encephalitis. A mutation in the chemokine receptor 5 (CCR5) gene has been associated with increased risk of TBE but can only explain a limited number of cases and investigations of further risk factors are clearly needed. To investigate the importance of the innate immune response, 128 Lithuanian TBE patients with meningitis or encephalitis, 77 patients with aseptic meningoencephalitis (AME) and 135 healthy controls were analyzed for three mutations: two in the toll‐like receptor 3 (TLR3) gene and one in the 2´‐5´ oligoadenylate synthetase 1 (OAS1) gene. While no association was found between the mutation in OAS1 and TBE, the genotype distribution of one of the mutations in TLR3, rs3775291, differed significantly between the TBE patients and the controls. 61%, 32% and 7% of the TBE patients (n=127) were carriers of the wild‐type/wild‐type, heterozygous and mutant/mutant genotype of TLR3 rs3775291 genotype respectively. The corresponding percentages for healthy controls (n=126) were 52%, 29% and 19% (P=0.02) and for AME patients (n=75) 47%, 32% and 21% (P=0.009). The wild‐type rs3775291 allele was more common among TBE patients than healthy controls (allele frequency 0.768 vs. 0.663, P=0.01), suggesting that functional TLR3 is a risk factor for severe TBEV infection.