CORD-19-Sentences  

CORD-19:9c983db27cc8ff3e50008d8d2bc803e14da7d38b JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
TextSentencer_T1 0-179 Sentence denotes Mice with different susceptibility to tick-borne encephalitis virus infection show selective neutralizing antibody response and inflammatory reaction in the central nervous system
TextSentencer_T1 0-179 Sentence denotes Mice with different susceptibility to tick-borne encephalitis virus infection show selective neutralizing antibody response and inflammatory reaction in the central nervous system
TextSentencer_T2 181-189 Sentence denotes Abstract
TextSentencer_T2 181-189 Sentence denotes Abstract
TextSentencer_T3 190-390 Sentence denotes The clinical course of tick-borne encephalitis (TBE), a disease caused by TBE virus, ranges from asymptomatic or mild influenza-like infection to severe debilitating encephalitis or encephalomyelitis.
TextSentencer_T3 190-390 Sentence denotes The clinical course of tick-borne encephalitis (TBE), a disease caused by TBE virus, ranges from asymptomatic or mild influenza-like infection to severe debilitating encephalitis or encephalomyelitis.
TextSentencer_T4 391-518 Sentence denotes Despite the medical importance of this disease, some crucial steps in the development of encephalitis remain poorly understood.
TextSentencer_T4 391-518 Sentence denotes Despite the medical importance of this disease, some crucial steps in the development of encephalitis remain poorly understood.
TextSentencer_T5 519-587 Sentence denotes In particular, the basis of the disease severity is largely unknown.
TextSentencer_T5 519-587 Sentence denotes In particular, the basis of the disease severity is largely unknown.
TextSentencer_T6 588-852 Sentence denotes Methods: TBE virus growth, neutralizing antibody response, key cytokine and chemokine mRNA production and changes in mRNA levels of cell surface markers of immunocompetent cells in brain were measured in mice with different susceptibilities to TBE virus infection.
TextSentencer_T6 588-852 Sentence denotes Methods: TBE virus growth, neutralizing antibody response, key cytokine and chemokine mRNA production and changes in mRNA levels of cell surface markers of immunocompetent cells in brain were measured in mice with different susceptibilities to TBE virus infection.
TextSentencer_T7 853-956 Sentence denotes showing different severities of the infection in relation to the host genetic background was developed.
TextSentencer_T7 853-956 Sentence denotes showing different severities of the infection in relation to the host genetic background was developed.
TextSentencer_T8 957-1126 Sentence denotes After subcutaneous inoculation of TBE virus, BALB/c mice showed medium susceptibility to the infection, STS mice were resistant, and CcS-11 mice were highly susceptible.
TextSentencer_T8 957-1126 Sentence denotes After subcutaneous inoculation of TBE virus, BALB/c mice showed medium susceptibility to the infection, STS mice were resistant, and CcS-11 mice were highly susceptible.
TextSentencer_T9 1127-1312 Sentence denotes The resistant STS mice showed lower and delayed viremia, lower virus production in the brain and low cytokine/chemokine mRNA production, but had a strong neutralizing antibody response.
TextSentencer_T9 1127-1312 Sentence denotes The resistant STS mice showed lower and delayed viremia, lower virus production in the brain and low cytokine/chemokine mRNA production, but had a strong neutralizing antibody response.
TextSentencer_T10 1313-1466 Sentence denotes The most sensitive strain (CcS-11) failed in production of neutralizing antibodies, but exhibited strong cytokine/chemokine mRNA production in the brain.
TextSentencer_T10 1313-1466 Sentence denotes The most sensitive strain (CcS-11) failed in production of neutralizing antibodies, but exhibited strong cytokine/chemokine mRNA production in the brain.
TextSentencer_T11 1467-1657 Sentence denotes After intracerebral inoculation, all mouse strains were sensitive to the infection and had similar virus production in the brain, but STS mice survived significantly longer than CcS-11 mice.
TextSentencer_T11 1467-1657 Sentence denotes After intracerebral inoculation, all mouse strains were sensitive to the infection and had similar virus production in the brain, but STS mice survived significantly longer than CcS-11 mice.
TextSentencer_T12 1658-1862 Sentence denotes These two strains also differed in the expression of key cytokines/chemokines, particularly interferon gamma-induced protein 10 (IP-10/CXCL10) and monocyte chemotactic protein-1 (MCP-1/CCL2) in the brain.
TextSentencer_T12 1658-1862 Sentence denotes These two strains also differed in the expression of key cytokines/chemokines, particularly interferon gamma-induced protein 10 (IP-10/CXCL10) and monocyte chemotactic protein-1 (MCP-1/CCL2) in the brain.
TextSentencer_T13 1863-1968 Sentence denotes Our data indicate that the genetic control is an important factor influencing the clinical course of TBE.
TextSentencer_T13 1863-1968 Sentence denotes Our data indicate that the genetic control is an important factor influencing the clinical course of TBE.
TextSentencer_T14 1969-2225 Sentence denotes High neutralizing antibody response might be crucial for preventing host fatality, but high expression of various cytokines/chemokines during TBE can mediate immunopathology and be associated with more severe course of the infection and increased fatality.
TextSentencer_T14 1969-2225 Sentence denotes High neutralizing antibody response might be crucial for preventing host fatality, but high expression of various cytokines/chemokines during TBE can mediate immunopathology and be associated with more severe course of the infection and increased fatality.
TextSentencer_T15 2227-2366 Sentence denotes Flaviviruses, a group of small, enveloped, positive-sense, single-stranded RNA viruses, include several medically very important pathogens.
TextSentencer_T15 2227-2366 Sentence denotes Flaviviruses, a group of small, enveloped, positive-sense, single-stranded RNA viruses, include several medically very important pathogens.
TextSentencer_T16 2367-2661 Sentence denotes Especially Japanese encephalitis virus, yellow fever virus, West Nile virus, dengue virus, Murray Valley encephalitis virus and tick-borne encephalitis virus (TBEV) are responsible for large outbreaks of fatal encephalitis or hemorrhagic fevers at diverse geographical regions around the world.
TextSentencer_T16 2367-2661 Sentence denotes Especially Japanese encephalitis virus, yellow fever virus, West Nile virus, dengue virus, Murray Valley encephalitis virus and tick-borne encephalitis virus (TBEV) are responsible for large outbreaks of fatal encephalitis or hemorrhagic fevers at diverse geographical regions around the world.
TextSentencer_T17 2662-2816 Sentence denotes Tick-borne encephalitis (TBE), a disease caused by TBEV, represents one of the most important and serious neuroinfections in Europe and northeastern Asia.
TextSentencer_T17 2662-2816 Sentence denotes Tick-borne encephalitis (TBE), a disease caused by TBEV, represents one of the most important and serious neuroinfections in Europe and northeastern Asia.
TextSentencer_T18 2817-2906 Sentence denotes More than 13,000 clinical cases of TBE, including numerous deaths, are reported annually.
TextSentencer_T18 2817-2906 Sentence denotes More than 13,000 clinical cases of TBE, including numerous deaths, are reported annually.
TextSentencer_T19 2907-3034 Sentence denotes Despite the medical importance of this disease, some crucial steps in the development of encephalitis remain poorly understood.
TextSentencer_T19 2907-3034 Sentence denotes Despite the medical importance of this disease, some crucial steps in the development of encephalitis remain poorly understood.
TextSentencer_T20 3035-3199 Sentence denotes In humans, TBEV may produce a variety of clinical symptoms, from an asymptomatic disease (70-90% of cases) to a fever and acute or chronic progressive encephalitis.
TextSentencer_T20 3035-3199 Sentence denotes In humans, TBEV may produce a variety of clinical symptoms, from an asymptomatic disease (70-90% of cases) to a fever and acute or chronic progressive encephalitis.
TextSentencer_T21 3200-3416 Sentence denotes This is influenced by a variety of factors, e.g., the inoculation dose and virulence of the virus [1] , the age, sex and immune status of the host [2] , and also susceptibility based on the host's genetic background.
TextSentencer_T21 3200-3416 Sentence denotes This is influenced by a variety of factors, e.g., the inoculation dose and virulence of the virus [1] , the age, sex and immune status of the host [2] , and also susceptibility based on the host's genetic background.
TextSentencer_T22 3417-3691 Sentence denotes Studies of animal models and epidemiological studies in humans have shown that many apparently non-hereditary diseases, including infectious diseases, develop predominantly in genetically predisposed individuals and that this predisposition is caused by multiple genes [3] .
TextSentencer_T22 3417-3691 Sentence denotes Studies of animal models and epidemiological studies in humans have shown that many apparently non-hereditary diseases, including infectious diseases, develop predominantly in genetically predisposed individuals and that this predisposition is caused by multiple genes [3] .
TextSentencer_T23 3692-3787 Sentence denotes In humans, a functional Toll-like receptor 3 gene may be a risk factor for TBEV infection [4] .
TextSentencer_T23 3692-3787 Sentence denotes In humans, a functional Toll-like receptor 3 gene may be a risk factor for TBEV infection [4] .
TextSentencer_T24 3788-4043 Sentence denotes A deletion within the chemokine receptor CCR5 (CCR5Δ32), which plays an important role in leukocyte transmigration across the blood-brain barrier, is significantly more frequent in patients with TBE than in TBE-naïve patients with aseptic meningitis [5] .
TextSentencer_T24 3788-4043 Sentence denotes A deletion within the chemokine receptor CCR5 (CCR5Δ32), which plays an important role in leukocyte transmigration across the blood-brain barrier, is significantly more frequent in patients with TBE than in TBE-naïve patients with aseptic meningitis [5] .
TextSentencer_T25 4044-4409 Sentence denotes Moreover, the severity and outcome of TBE is associated with variability in the 2'-5'-oligoadenylate synthetase gene cluster (family members are interferoninduced antiviral proteins that play an important role in the endogenous antiviral pathway) [6] and with the rs2287886 single nucleotide polymorphism located in the promoter region of the human CD209 gene [7] .
TextSentencer_T25 4044-4409 Sentence denotes Moreover, the severity and outcome of TBE is associated with variability in the 2'-5'-oligoadenylate synthetase gene cluster (family members are interferoninduced antiviral proteins that play an important role in the endogenous antiviral pathway) [6] and with the rs2287886 single nucleotide polymorphism located in the promoter region of the human CD209 gene [7] .
TextSentencer_T26 4410-4614 Sentence denotes This gene encodes dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN), a C-type lectin pathogenrecognition receptor expressed on the surface of dendritic cells and some types of macrophages [7] .
TextSentencer_T26 4410-4614 Sentence denotes This gene encodes dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN), a C-type lectin pathogenrecognition receptor expressed on the surface of dendritic cells and some types of macrophages [7] .
TextSentencer_T27 4615-4771 Sentence denotes Taken together, polymorphism in various genes may largely influence the sensitivity of the host to the infection and determine the severity of this disease.
TextSentencer_T27 4615-4771 Sentence denotes Taken together, polymorphism in various genes may largely influence the sensitivity of the host to the infection and determine the severity of this disease.
TextSentencer_T28 4772-4980 Sentence denotes While in humans involvement of genetic factors in the control of the susceptibility to TBEV infection is quite difficult to investigate, mice provide a useful small animal model for such a kind of study [8] .
TextSentencer_T28 4772-4980 Sentence denotes While in humans involvement of genetic factors in the control of the susceptibility to TBEV infection is quite difficult to investigate, mice provide a useful small animal model for such a kind of study [8] .
TextSentencer_T29 4981-5141 Sentence denotes Mice are suitable animal models of infection with TBEV because they can reproduce symptoms and physiopathological markers as observed in severe cases in humans.
TextSentencer_T29 4981-5141 Sentence denotes Mice are suitable animal models of infection with TBEV because they can reproduce symptoms and physiopathological markers as observed in severe cases in humans.
TextSentencer_T30 5142-5351 Sentence denotes A high susceptibility of most laboratory mouse strains to flavivirus infection has been genetically mapped to a stop codon mutation in the coding region of the 2´-5´-oligoadenylate synthetase gene Oas 1b [9] .
TextSentencer_T30 5142-5351 Sentence denotes A high susceptibility of most laboratory mouse strains to flavivirus infection has been genetically mapped to a stop codon mutation in the coding region of the 2´-5´-oligoadenylate synthetase gene Oas 1b [9] .
TextSentencer_T31 5352-5562 Sentence denotes In our study, we developed an animal model of TBE showing several manifestations of the disease in relation to the genetic background, which is not based on the previously published mutation in the Oas 1b gene.
TextSentencer_T31 5352-5562 Sentence denotes In our study, we developed an animal model of TBE showing several manifestations of the disease in relation to the genetic background, which is not based on the previously published mutation in the Oas 1b gene.
TextSentencer_T32 5563-5742 Sentence denotes We analyzed the sensitivity to TBEV in CcS/Dem (CcS) recombinant congenic (RC) strains of mice [10] derived from the background strain BALB/cHeA (BALB/c) and the donor strain STS.
TextSentencer_T32 5563-5742 Sentence denotes We analyzed the sensitivity to TBEV in CcS/Dem (CcS) recombinant congenic (RC) strains of mice [10] derived from the background strain BALB/cHeA (BALB/c) and the donor strain STS.
TextSentencer_T33 5743-5891 Sentence denotes Each CcS strain contains a unique random set of about 12.5% genes from the donor strain STS and 87.5% genes from the background strain BALB/c [10] .
TextSentencer_T33 5743-5891 Sentence denotes Each CcS strain contains a unique random set of about 12.5% genes from the donor strain STS and 87.5% genes from the background strain BALB/c [10] .
TextSentencer_T34 5892-6061 Sentence denotes This system has been very useful in research of bacterial [11] and parasitic [12] [13] [14] [15] [16] [17] [18] diseases, as well as in cancer [19] [20] [21] [22] [23] .
TextSentencer_T34 5892-6061 Sentence denotes This system has been very useful in research of bacterial [11] and parasitic [12] [13] [14] [15] [16] [17] [18] diseases, as well as in cancer [19] [20] [21] [22] [23] .
TextSentencer_T35 6062-6175 Sentence denotes In this study, we identified mouse strains that exhibit high, intermediate and low sensitivity to TBEV infection.
TextSentencer_T35 6062-6175 Sentence denotes In this study, we identified mouse strains that exhibit high, intermediate and low sensitivity to TBEV infection.
TextSentencer_T36 6176-6295 Sentence denotes Virus growth, key cytokine and chemokine mRNA production in the brain and neutralizing antibody response were measured.
TextSentencer_T36 6176-6295 Sentence denotes Virus growth, key cytokine and chemokine mRNA production in the brain and neutralizing antibody response were measured.
TextSentencer_T37 6296-6557 Sentence denotes Our data suggest that the genetic control represents one of the important factors that influence the clinical course of TBE and that also other genes than the previously described Oas 1b are involved in the determination of host susceptibility to the infection.
TextSentencer_T37 6296-6557 Sentence denotes Our data suggest that the genetic control represents one of the important factors that influence the clinical course of TBE and that also other genes than the previously described Oas 1b are involved in the determination of host susceptibility to the infection.
TextSentencer_T38 6558-6822 Sentence denotes While high neutralizing antibody response might be crucial for preventing host fatality, high local expression of various proinflammatory cytokines/chemokines in the brain during TBE can be associated with a more severe course of the infection and higher fatality.
TextSentencer_T38 6558-6822 Sentence denotes While high neutralizing antibody response might be crucial for preventing host fatality, high local expression of various proinflammatory cytokines/chemokines in the brain during TBE can be associated with a more severe course of the infection and higher fatality.
TextSentencer_T39 6823-6958 Sentence denotes Our data may be instrumental in the development of future therapeutic strategies aimed at treating or preventing TBE neuropathogenesis.
TextSentencer_T39 6823-6958 Sentence denotes Our data may be instrumental in the development of future therapeutic strategies aimed at treating or preventing TBE neuropathogenesis.
TextSentencer_T40 6959-7097 Sentence denotes Specific pathogen-free mice of parental strains BALB/c, STS and ten randomly selected RC strains (see below) were used in the experiments.
TextSentencer_T40 6959-7097 Sentence denotes Specific pathogen-free mice of parental strains BALB/c, STS and ten randomly selected RC strains (see below) were used in the experiments.
TextSentencer_T41 7098-7187 Sentence denotes RC strains were in more than 90 generation of inbreeding and therefore highly homozygous.
TextSentencer_T41 7098-7187 Sentence denotes RC strains were in more than 90 generation of inbreeding and therefore highly homozygous.
TextSentencer_T42 7188-7266 Sentence denotes Genetic composition of the strain CcS-11 is schematically shown in Figure 1A .
TextSentencer_T42 7188-7266 Sentence denotes Genetic composition of the strain CcS-11 is schematically shown in Figure 1A .
TextSentencer_T43 7267-7325 Sentence denotes Sterilized pellet diet and water were supplied ad libitum.
TextSentencer_T43 7267-7325 Sentence denotes Sterilized pellet diet and water were supplied ad libitum.
TextSentencer_T44 7326-7410 Sentence denotes In all experiments, female mice aged 12-15 weeks at the time of infection were used.
TextSentencer_T44 7326-7410 Sentence denotes In all experiments, female mice aged 12-15 weeks at the time of infection were used.
TextSentencer_T45 7411-7582 Sentence denotes The mice were housed in plastic cages with wood-chip bedding, situated in a specific pathogen-free room with a constant temperature of 22°C and a relative humidity of 65%.
TextSentencer_T45 7411-7582 Sentence denotes The mice were housed in plastic cages with wood-chip bedding, situated in a specific pathogen-free room with a constant temperature of 22°C and a relative humidity of 65%.
TextSentencer_T46 7583-7836 Sentence denotes The research complied with all relevant European Union guidelines for work with animals and was in accordance with the Czech national law and guidelines on the use of experimental animals and protection of animals against cruelty (Animal Welfare Act no.
TextSentencer_T46 7583-7836 Sentence denotes The research complied with all relevant European Union guidelines for work with animals and was in accordance with the Czech national law and guidelines on the use of experimental animals and protection of animals against cruelty (Animal Welfare Act no.
TextSentencer_T47 7837-7853 Sentence denotes 246/1992 Coll.).
TextSentencer_T47 7837-7853 Sentence denotes 246/1992 Coll.).
TextSentencer_T48 7854-8122 Sentence denotes The protocol was approved by the Committee on the Ethics of Animal Experiments of the Institute of Parasitology and of the Departmental Expert Committee for the Approval of Projects of Experiments on Animals of the Academy of Sciences of the Czech Republic (permit no.
TextSentencer_T48 7854-8122 Sentence denotes The protocol was approved by the Committee on the Ethics of Animal Experiments of the Institute of Parasitology and of the Departmental Expert Committee for the Approval of Projects of Experiments on Animals of the Academy of Sciences of the Czech Republic (permit no.
TextSentencer_T49 8123-8133 Sentence denotes 165/2010).
TextSentencer_T49 8123-8133 Sentence denotes 165/2010).
TextSentencer_T50 8134-8239 Sentence denotes All experiments were performed with European prototypic TBEV strain Neudoerfl (a generous gift from Prof.
TextSentencer_T50 8134-8239 Sentence denotes All experiments were performed with European prototypic TBEV strain Neudoerfl (a generous gift from Prof.
TextSentencer_T51 8240-8244 Sentence denotes F.X.
TextSentencer_T51 8240-8244 Sentence denotes F.X.
TextSentencer_T52 8245-8282 Sentence denotes Heinz, Medical University of Vienna).
TextSentencer_T52 8245-8282 Sentence denotes Heinz, Medical University of Vienna).
TextSentencer_T53 8283-8530 Sentence denotes The virus was originally isolated from the tick Ixodes ricinus in Austria in 1971 and has been extensively characterized including its complete genome sequence and the determination of the three-dimensional structure of its envelope protein [24] .
TextSentencer_T53 8283-8530 Sentence denotes The virus was originally isolated from the tick Ixodes ricinus in Austria in 1971 and has been extensively characterized including its complete genome sequence and the determination of the three-dimensional structure of its envelope protein [24] .
TextSentencer_T54 8531-8594 Sentence denotes This strain was passaged four times in brains of suckling mice.
TextSentencer_T54 8531-8594 Sentence denotes This strain was passaged four times in brains of suckling mice.
TextSentencer_T55 8595-8736 Sentence denotes Mice were infected either subcutaneously (s.c.) into the scruff of the neck with 10 3 pfu or intracerebrally (i.c.) with 10 pfu of the virus.
TextSentencer_T55 8595-8736 Sentence denotes Mice were infected either subcutaneously (s.c.) into the scruff of the neck with 10 3 pfu or intracerebrally (i.c.) with 10 pfu of the virus.
TextSentencer_T56 8737-8852 Sentence denotes Mice were scored for mortality for a period of 28 days post-infection (p.i.), and survival curves were established.
TextSentencer_T56 8737-8852 Sentence denotes Mice were scored for mortality for a period of 28 days post-infection (p.i.), and survival curves were established.
TextSentencer_T57 8853-9019 Sentence denotes The virus titers were determined by plaque assay on porcine kidney stable cell (PS) monolayers under a carboxymethyl-cellulose overlay, as described previously [25] .
TextSentencer_T57 8853-9019 Sentence denotes The virus titers were determined by plaque assay on porcine kidney stable cell (PS) monolayers under a carboxymethyl-cellulose overlay, as described previously [25] .
TextSentencer_T58 9020-9106 Sentence denotes Infectivity was expressed as plaque-forming units (pfu) per ml (or g of brain tissue).
TextSentencer_T58 9020-9106 Sentence denotes Infectivity was expressed as plaque-forming units (pfu) per ml (or g of brain tissue).
TextSentencer_T59 9107-9215 Sentence denotes At the given time point p.i., three mice of each group were anesthetized and killed by cervical dislocation.
TextSentencer_T59 9107-9215 Sentence denotes At the given time point p.i., three mice of each group were anesthetized and killed by cervical dislocation.
TextSentencer_T60 9216-9267 Sentence denotes Specimens of blood serum and brains were collected.
TextSentencer_T60 9216-9267 Sentence denotes Specimens of blood serum and brains were collected.
TextSentencer_T61 9268-9398 Sentence denotes Brains were individually weighed and prepared as 20% suspensions in phosphate-buffered saline (PBS) using TissueLyser II (Qiagen).
TextSentencer_T61 9268-9398 Sentence denotes Brains were individually weighed and prepared as 20% suspensions in phosphate-buffered saline (PBS) using TissueLyser II (Qiagen).
TextSentencer_T62 9399-9543 Sentence denotes The homogenate was clarified by centrifugation at 14,000× g for 10 min at 4°C, and supernatant fluids were titrated by plaque assay on PS cells.
TextSentencer_T62 9399-9543 Sentence denotes The homogenate was clarified by centrifugation at 14,000× g for 10 min at 4°C, and supernatant fluids were titrated by plaque assay on PS cells.
TextSentencer_T63 9544-9645 Sentence denotes The detection thresholds were 1.4 log 10 pfu/ml for serum and 2.1 log 10 pfu/g for brain suspensions.
TextSentencer_T63 9544-9645 Sentence denotes The detection thresholds were 1.4 log 10 pfu/ml for serum and 2.1 log 10 pfu/g for brain suspensions.
TextSentencer_T64 9646-9775 Sentence denotes Real-time quantitative PCR was performed by the TaqMan Gene Expression Assays (Applied Biosystems) as previously described [26] .
TextSentencer_T64 9646-9775 Sentence denotes Real-time quantitative PCR was performed by the TaqMan Gene Expression Assays (Applied Biosystems) as previously described [26] .
TextSentencer_T65 9776-10031 Sentence denotes RNA was isolated from the brain tissue pellets using RNeasy Mini Kit (Qiagen), according to the recommendations of the manufacturer. cDNA was synthesized using a High Capacity RNA-to-cDNA Kit (Applied Biosystems), according to the manufacturer's protocol.
TextSentencer_T65 9776-10031 Sentence denotes RNA was isolated from the brain tissue pellets using RNeasy Mini Kit (Qiagen), according to the recommendations of the manufacturer. cDNA was synthesized using a High Capacity RNA-to-cDNA Kit (Applied Biosystems), according to the manufacturer's protocol.
TextSentencer_T66 10032-10095 Sentence denotes The synthesized cDNAs were used as templates for real-time PCR.
TextSentencer_T66 10032-10095 Sentence denotes The synthesized cDNAs were used as templates for real-time PCR.
TextSentencer_T67 10096-10363 Sentence denotes In quantitative RT-PCR the following primer probe sets from Applied Biosystems were used: TNFα (Mm00443258_m1), IFNγ Quantification of gene expression was performed using the comparative CT method and reported as the fold difference relative to the housekeeping gene.
TextSentencer_T67 10096-10363 Sentence denotes In quantitative RT-PCR the following primer probe sets from Applied Biosystems were used: TNFα (Mm00443258_m1), IFNγ Quantification of gene expression was performed using the comparative CT method and reported as the fold difference relative to the housekeeping gene.
TextSentencer_T68 10364-10489 Sentence denotes To calculate the fold change, the CT of the housekeeping gene was subtracted from the CT of the target gene to yield the ΔCT.
TextSentencer_T68 10364-10489 Sentence denotes To calculate the fold change, the CT of the housekeeping gene was subtracted from the CT of the target gene to yield the ΔCT.
TextSentencer_T69 10490-10635 Sentence denotes Change in expression of the normalized target gene was expressed as 2 -ΔΔCT where ΔΔCT = ΔCT samples -ΔCT controls as previously described [27] .
TextSentencer_T69 10490-10635 Sentence denotes Change in expression of the normalized target gene was expressed as 2 -ΔΔCT where ΔΔCT = ΔCT samples -ΔCT controls as previously described [27] .
TextSentencer_T70 10636-10822 Sentence denotes The titers of neutralizing antibodies against TBEV in mouse sera were determined by the plaque reduction neutralization test (PRNT) as described by Bárdoš [28] with slight modifications.
TextSentencer_T70 10636-10822 Sentence denotes The titers of neutralizing antibodies against TBEV in mouse sera were determined by the plaque reduction neutralization test (PRNT) as described by Bárdoš [28] with slight modifications.
TextSentencer_T71 10823-11043 Sentence denotes Sera (including positive and negative controls) were diluted 1:4 in L-15 medium (Leibowitz; Sigma) supplemented with 1% antibiotics (penicillin, streptomycin, amphotericin B; Sigma) and 3% inactivated newborn calf serum.
TextSentencer_T71 10823-11043 Sentence denotes Sera (including positive and negative controls) were diluted 1:4 in L-15 medium (Leibowitz; Sigma) supplemented with 1% antibiotics (penicillin, streptomycin, amphotericin B; Sigma) and 3% inactivated newborn calf serum.
TextSentencer_T72 11044-11385 Sentence denotes After inactivation of the virus and complement in the sera by heating at 56°C for 30 min, two-fold serial dilutions of the samples in L-15 medium were incubated with 10 3 pfu of TBEV (the virus test dose was adjusted so that it caused almost confluent plaques, 90-95% cytolysis) for 90 min at 37°C; 5 × 10 4 PS cells were added to each well.
TextSentencer_T72 11044-11385 Sentence denotes After inactivation of the virus and complement in the sera by heating at 56°C for 30 min, two-fold serial dilutions of the samples in L-15 medium were incubated with 10 3 pfu of TBEV (the virus test dose was adjusted so that it caused almost confluent plaques, 90-95% cytolysis) for 90 min at 37°C; 5 × 10 4 PS cells were added to each well.
TextSentencer_T73 11386-11510 Sentence denotes After 6 days of incubation, the cell supernatant was removed and cells were fixed and stained as described previously [25] .
TextSentencer_T73 11386-11510 Sentence denotes After 6 days of incubation, the cell supernatant was removed and cells were fixed and stained as described previously [25] .
TextSentencer_T74 11511-11639 Sentence denotes The last dilution of serum that caused an 80-100% reduction in cytolysis of the virus test dose was regarded as the serum titer.
TextSentencer_T74 11511-11639 Sentence denotes The last dilution of serum that caused an 80-100% reduction in cytolysis of the virus test dose was regarded as the serum titer.
TextSentencer_T75 11640-11752 Sentence denotes The differences in survival time of infected mice were analyzed by survival analysis (log-rank Mantel-Cox test).
TextSentencer_T75 11640-11752 Sentence denotes The differences in survival time of infected mice were analyzed by survival analysis (log-rank Mantel-Cox test).
TextSentencer_T76 11753-11839 Sentence denotes All other data were analyzed by one-way ANOVA (Newman-Keuls multiple comparison test).
TextSentencer_T76 11753-11839 Sentence denotes All other data were analyzed by one-way ANOVA (Newman-Keuls multiple comparison test).
TextSentencer_T77 11840-11923 Sentence denotes Data without normal distribution were transformed by use of the X' = ln(X) formula.
TextSentencer_T77 11840-11923 Sentence denotes Data without normal distribution were transformed by use of the X' = ln(X) formula.
TextSentencer_T78 11924-12054 Sentence denotes All analyses were performed using GraphPad Prism 5.00 (GraphPad Software, Inc., USA); p-values < 0.05 were considered significant.
TextSentencer_T78 11924-12054 Sentence denotes All analyses were performed using GraphPad Prism 5.00 (GraphPad Software, Inc., USA); p-values < 0.05 were considered significant.
TextSentencer_T79 12055-12263 Sentence denotes To study the susceptibility of mice to TBEV, we infected females of the strains BALB/c, STS and RC strains CcS-3, CcS-7, CcS-9, CcS-11, CcS-15 and CcS-16 s.c. with 10 4 pfu of TBEV, and survival was recorded.
TextSentencer_T79 12055-12263 Sentence denotes To study the susceptibility of mice to TBEV, we infected females of the strains BALB/c, STS and RC strains CcS-3, CcS-7, CcS-9, CcS-11, CcS-15 and CcS-16 s.c. with 10 4 pfu of TBEV, and survival was recorded.
TextSentencer_T80 12264-12358 Sentence denotes Mice with different genotypes exhibited different susceptibilities to TBEV (Additional file 1:
TextSentencer_T80 12264-12358 Sentence denotes Mice with different genotypes exhibited different susceptibilities to TBEV (Additional file 1:
TextSentencer_T81 12359-12371 Sentence denotes Figure S1 ).
TextSentencer_T81 12359-12371 Sentence denotes Figure S1 ).
TextSentencer_T82 12372-12525 Sentence denotes The most striking differences in survival rates and mean survival times were seen in parental strains BALB/c and STS, and RC strain CcS-11 ( Figure 1B ).
TextSentencer_T82 12372-12525 Sentence denotes The most striking differences in survival rates and mean survival times were seen in parental strains BALB/c and STS, and RC strain CcS-11 ( Figure 1B ).
TextSentencer_T83 12526-12614 Sentence denotes CcS-11 mice were shown to be most susceptible, while STS mice are the least susceptible.
TextSentencer_T83 12526-12614 Sentence denotes CcS-11 mice were shown to be most susceptible, while STS mice are the least susceptible.
TextSentencer_T84 12615-12665 Sentence denotes BALB/c mice exhibited intermediate susceptibility.
TextSentencer_T84 12615-12665 Sentence denotes BALB/c mice exhibited intermediate susceptibility.
TextSentencer_T85 12666-12787 Sentence denotes Mean survival time (MST) of the CcS-11 mice was 13.1 ± 3 days, BALB/c 22.8 ± 7.5 days and STS 29.7 ± 4.1 days (p < 0.05).
TextSentencer_T85 12666-12787 Sentence denotes Mean survival time (MST) of the CcS-11 mice was 13.1 ± 3 days, BALB/c 22.8 ± 7.5 days and STS 29.7 ± 4.1 days (p < 0.05).
TextSentencer_T86 12788-12842 Sentence denotes Differences were also found in case of survival rates.
TextSentencer_T86 12788-12842 Sentence denotes Differences were also found in case of survival rates.
TextSentencer_T87 12843-12993 Sentence denotes While all CcS-11 mice died following the infection, 40% of infected BALB/c and 90% of STS mice survived until the end of the experiment ( Figure 1B ).
TextSentencer_T87 12843-12993 Sentence denotes While all CcS-11 mice died following the infection, 40% of infected BALB/c and 90% of STS mice survived until the end of the experiment ( Figure 1B ).
TextSentencer_T88 12994-13193 Sentence denotes STS mice remained free of any clinical signs of the disease during the whole experiment (including that one mice that died); BALB/c mice exhibited signs of rough fur, hunching or back limb paralysis.
TextSentencer_T88 12994-13193 Sentence denotes STS mice remained free of any clinical signs of the disease during the whole experiment (including that one mice that died); BALB/c mice exhibited signs of rough fur, hunching or back limb paralysis.
TextSentencer_T89 13194-13308 Sentence denotes Some CcS-11 mice had similar signs as BALB/c mice, but some died without previous appearance of any kind of signs.
TextSentencer_T89 13194-13308 Sentence denotes Some CcS-11 mice had similar signs as BALB/c mice, but some died without previous appearance of any kind of signs.
TextSentencer_T90 13309-13590 Sentence denotes In order to test the susceptibility to the TBEV infection if host factors before viral entry of the CNS are avoided, we infected females of the strains BALB/c, STS and RC strains CcS-3, CcS-4, CcS-5, CcS-7, CcS-9, CcS-11, CcS-12, CcS-15, CcS-18 and CcS-20 i.c. with 10 pfu of TBEV.
TextSentencer_T90 13309-13590 Sentence denotes In order to test the susceptibility to the TBEV infection if host factors before viral entry of the CNS are avoided, we infected females of the strains BALB/c, STS and RC strains CcS-3, CcS-4, CcS-5, CcS-7, CcS-9, CcS-11, CcS-12, CcS-15, CcS-18 and CcS-20 i.c. with 10 pfu of TBEV.
TextSentencer_T91 13591-13657 Sentence denotes In this case, all mouse strains were susceptible to the infection.
TextSentencer_T91 13591-13657 Sentence denotes In this case, all mouse strains were susceptible to the infection.
TextSentencer_T92 13658-13759 Sentence denotes Most strains died almost at the same time p.i., i.e., between days 10 and 11 p.i. (Additional file 1:
TextSentencer_T92 13658-13759 Sentence denotes Most strains died almost at the same time p.i., i.e., between days 10 and 11 p.i. (Additional file 1:
TextSentencer_T93 13760-13772 Sentence denotes Figure S2 ).
TextSentencer_T93 13760-13772 Sentence denotes Figure S2 ).
TextSentencer_T94 13773-13953 Sentence denotes However, differences were seen in the MST in case of CcS-11 (MST of 8.0 ± 0.7 days), BALB/c (MST of 9.5 ± 0.5 days) and STS strains (MST of 12.4 ± 2.7 days) (p < 0.05; Figure 1C ).
TextSentencer_T94 13773-13953 Sentence denotes However, differences were seen in the MST in case of CcS-11 (MST of 8.0 ± 0.7 days), BALB/c (MST of 9.5 ± 0.5 days) and STS strains (MST of 12.4 ± 2.7 days) (p < 0.05; Figure 1C ).
TextSentencer_T95 13954-14058 Sentence denotes Therefore, also factors acting directly in the CNS of the infected mice may influence the survival time.
TextSentencer_T95 13954-14058 Sentence denotes Therefore, also factors acting directly in the CNS of the infected mice may influence the survival time.
TextSentencer_T96 14059-14205 Sentence denotes For all subsequent experiments, mice of strains CcS-11, BALB/c and STS were selected as representatives of high-, medium-and lowsusceptible hosts.
TextSentencer_T96 14059-14205 Sentence denotes For all subsequent experiments, mice of strains CcS-11, BALB/c and STS were selected as representatives of high-, medium-and lowsusceptible hosts.
TextSentencer_T97 14206-14334 Sentence denotes Serum samples of BALB/c, CcS-11 and STS mice were harvested for titration at various time points after s.c. inoculation of TBEV.
TextSentencer_T97 14206-14334 Sentence denotes Serum samples of BALB/c, CcS-11 and STS mice were harvested for titration at various time points after s.c. inoculation of TBEV.
TextSentencer_T98 14335-14418 Sentence denotes The virus titers in individual samples were determined by plaque assay on PS cells.
TextSentencer_T98 14335-14418 Sentence denotes The virus titers in individual samples were determined by plaque assay on PS cells.
TextSentencer_T99 14419-14604 Sentence denotes While the peak of viremia was observed in BALB/c and CcS-11 mice reaching 2-2.5 log 10 pfu/ml at days 3 and 4 p.i., no virus was detected at the same time points in STS mice (p < 0.05).
TextSentencer_T99 14419-14604 Sentence denotes While the peak of viremia was observed in BALB/c and CcS-11 mice reaching 2-2.5 log 10 pfu/ml at days 3 and 4 p.i., no virus was detected at the same time points in STS mice (p < 0.05).
TextSentencer_T100 14605-14737 Sentence denotes STS mice had only traces of the virus in serum (<2 log 10 pfu/ml) at later time intervals, i.e. at day 5, 6 and 8 p.i. (Figure 2A ).
TextSentencer_T100 14605-14737 Sentence denotes STS mice had only traces of the virus in serum (<2 log 10 pfu/ml) at later time intervals, i.e. at day 5, 6 and 8 p.i. (Figure 2A ).
TextSentencer_T101 14738-14936 Sentence denotes Virus load in the brain after s.c. inoculation was assayed at day 13 p.i., i.e. at the time point when most of the CcS-11 and BALB/c mice exhibited neurological signs of the infection ( Figure 2B) .
TextSentencer_T101 14738-14936 Sentence denotes Virus load in the brain after s.c. inoculation was assayed at day 13 p.i., i.e. at the time point when most of the CcS-11 and BALB/c mice exhibited neurological signs of the infection ( Figure 2B) .
TextSentencer_T102 14937-15172 Sentence denotes No difference was found in the virus titer in brain of the infected BALB/c and CcS-11 mice (titer reaching 6-7 log 10 pfu/g), but a much lower titer was observed in brains of infected STS mice (approximately 3 log 10 pfu/g; p < 0.005).
TextSentencer_T102 14937-15172 Sentence denotes No difference was found in the virus titer in brain of the infected BALB/c and CcS-11 mice (titer reaching 6-7 log 10 pfu/g), but a much lower titer was observed in brains of infected STS mice (approximately 3 log 10 pfu/g; p < 0.005).
TextSentencer_T103 15173-15254 Sentence denotes After i.c. inoculation, a dynamics of virus growth in the brain was investigated.
TextSentencer_T103 15173-15254 Sentence denotes After i.c. inoculation, a dynamics of virus growth in the brain was investigated.
TextSentencer_T104 15255-15331 Sentence denotes Increasing virus titers were seen before mice showed signs of the infection.
TextSentencer_T104 15255-15331 Sentence denotes Increasing virus titers were seen before mice showed signs of the infection.
TextSentencer_T105 15332-15459 Sentence denotes The virus growth was almost identical in all three mouse strains, reaching its maximum at day 7 (8 log 10 pfu/g) ( Figure 2C ).
TextSentencer_T105 15332-15459 Sentence denotes The virus growth was almost identical in all three mouse strains, reaching its maximum at day 7 (8 log 10 pfu/g) ( Figure 2C ).
TextSentencer_T106 15460-15594 Sentence denotes The only difference was observed at day 2, when BALB/c mice had slightly higher virus titers in the brain than CcS-11 mice (p < 0.05).
TextSentencer_T106 15460-15594 Sentence denotes The only difference was observed at day 2, when BALB/c mice had slightly higher virus titers in the brain than CcS-11 mice (p < 0.05).
TextSentencer_T107 15595-15878 Sentence denotes Accumulation of immunocompetent cells in the brain of the infected BALB/c, STS and BALB/c mice was quantified as the changes in mRNA levels of cell surface markers of B-cells (CD19), T-helper cells (CD4), cytotoxic T-cells (CD8β) and macrophage/monocyte/granulocyte/NK cells (CD11b).
TextSentencer_T107 15595-15878 Sentence denotes Accumulation of immunocompetent cells in the brain of the infected BALB/c, STS and BALB/c mice was quantified as the changes in mRNA levels of cell surface markers of B-cells (CD19), T-helper cells (CD4), cytotoxic T-cells (CD8β) and macrophage/monocyte/granulocyte/NK cells (CD11b).
TextSentencer_T108 15879-15998 Sentence denotes In case of s.c. inoculation of TBEV ( Figure 3A ), the immune cell antigen mRNA accumulation was assayed at day 13 p.i.
TextSentencer_T108 15879-15998 Sentence denotes In case of s.c. inoculation of TBEV ( Figure 3A ), the immune cell antigen mRNA accumulation was assayed at day 13 p.i.
TextSentencer_T109 15999-16109 Sentence denotes During our preliminary experiments, mice were also sampled and assayed at days 8 and 10 p.i. (data not shown).
TextSentencer_T109 15999-16109 Sentence denotes During our preliminary experiments, mice were also sampled and assayed at days 8 and 10 p.i. (data not shown).
TextSentencer_T110 16110-16211 Sentence denotes However, at these time points only some mice had virus in their CNS, making the results too variable.
TextSentencer_T110 16110-16211 Sentence denotes However, at these time points only some mice had virus in their CNS, making the results too variable.
TextSentencer_T111 16212-16291 Sentence denotes The day 13 p.i. was the first interval when all mice had virus in their brains.
TextSentencer_T111 16212-16291 Sentence denotes The day 13 p.i. was the first interval when all mice had virus in their brains.
TextSentencer_T112 16292-16450 Sentence denotes CD4, CD8β and CD11b mRNA levels in the brains of infected mice at day 13 p.i. became significantly higher than those of normal uninfected mice at day 13. p.i.
TextSentencer_T112 16292-16450 Sentence denotes CD4, CD8β and CD11b mRNA levels in the brains of infected mice at day 13 p.i. became significantly higher than those of normal uninfected mice at day 13. p.i.
TextSentencer_T113 16451-16578 Sentence denotes However, CD19 mRNA levels did not significantly increase in BALB/c and CcS-11 mice, but became elevated in STS mice (p < 0.05).
TextSentencer_T113 16451-16578 Sentence denotes However, CD19 mRNA levels did not significantly increase in BALB/c and CcS-11 mice, but became elevated in STS mice (p < 0.05).
TextSentencer_T114 16579-16720 Sentence denotes After i.c. inoculation of TBEV ( Figure 3B ), the dynamics of immune cell accumulation in the CNS was investigated at days 2, 4, 6 and 7 p.i.
TextSentencer_T114 16579-16720 Sentence denotes After i.c. inoculation of TBEV ( Figure 3B ), the dynamics of immune cell accumulation in the CNS was investigated at days 2, 4, 6 and 7 p.i.
TextSentencer_T115 16721-16841 Sentence denotes No significant increase in the CD19 mRNA levels was seen in any of the investigated mouse strain at 4, 6 and 7 days p.i.
TextSentencer_T115 16721-16841 Sentence denotes No significant increase in the CD19 mRNA levels was seen in any of the investigated mouse strain at 4, 6 and 7 days p.i.
TextSentencer_T116 16842-17003 Sentence denotes Levels of CD11b mRNA increased in brains of STS mice as early as at day 2 and 4 p.i., whereas no increase was observed in BALB/c and CcS-11 mice until day 4 p.i.
TextSentencer_T116 16842-17003 Sentence denotes Levels of CD11b mRNA increased in brains of STS mice as early as at day 2 and 4 p.i., whereas no increase was observed in BALB/c and CcS-11 mice until day 4 p.i.
TextSentencer_T117 17004-17169 Sentence denotes From day 6, a slight but significant increase of CD11b levels was observed in all mice tested; however, there was no difference between the individual mouse strains.
TextSentencer_T117 17004-17169 Sentence denotes From day 6, a slight but significant increase of CD11b levels was observed in all mice tested; however, there was no difference between the individual mouse strains.
TextSentencer_T118 17170-17368 Sentence denotes CD4 and CD8β mRNA levels increased remarkably (10-20-fold increase of CD4 mRNA and 100-200-fold increase of CD8β mRNA compared to negative controls) in all investigated mouse strains from day 6 p.i.
TextSentencer_T118 17170-17368 Sentence denotes CD4 and CD8β mRNA levels increased remarkably (10-20-fold increase of CD4 mRNA and 100-200-fold increase of CD8β mRNA compared to negative controls) in all investigated mouse strains from day 6 p.i.
TextSentencer_T119 17369-17500 Sentence denotes Higher levels of CD4 as well as CD8β mRNA levels were detected in brains of infected STS than BALB/c mice at day 6 p.i. (p < 0.05).
TextSentencer_T119 17369-17500 Sentence denotes Higher levels of CD4 as well as CD8β mRNA levels were detected in brains of infected STS than BALB/c mice at day 6 p.i. (p < 0.05).
TextSentencer_T120 17501-18124 Sentence denotes The levels of mRNA specific for a broad range of cytokines (TNF-α, IFNγ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6 and IL-10) and chemokines (CCL2 (chemokine ligand 2)/ MCP-1 (monocyte chemotactic protein-1), CCL3/MIP-1α (macrophage inflammatory protein-1α), CCL4/MIP-1β (macrophage inflammatory protein-1β), CCL5/RANTES (regulated upon activation, normal T-cell expressed and secreted) and interferon-γ-inducible protein-10 (IP-10)/ CXCL/10) were quantified in brains of TBEV infected BALB/c, CcS-11 and STS mice by real-time RT-PCR, and standardized to the levels of the housekeeping gene, beta actin, mRNA (Figures 4 and 5) .
TextSentencer_T120 17501-18124 Sentence denotes The levels of mRNA specific for a broad range of cytokines (TNF-α, IFNγ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6 and IL-10) and chemokines (CCL2 (chemokine ligand 2)/ MCP-1 (monocyte chemotactic protein-1), CCL3/MIP-1α (macrophage inflammatory protein-1α), CCL4/MIP-1β (macrophage inflammatory protein-1β), CCL5/RANTES (regulated upon activation, normal T-cell expressed and secreted) and interferon-γ-inducible protein-10 (IP-10)/ CXCL/10) were quantified in brains of TBEV infected BALB/c, CcS-11 and STS mice by real-time RT-PCR, and standardized to the levels of the housekeeping gene, beta actin, mRNA (Figures 4 and 5) .
TextSentencer_T121 18125-18239 Sentence denotes After the s.c. inoculation of TBEV (Figure 4) , the levels of cytokine/chemokine mRNA were measured on day 13 p.i.
TextSentencer_T121 18125-18239 Sentence denotes After the s.c. inoculation of TBEV (Figure 4) , the levels of cytokine/chemokine mRNA were measured on day 13 p.i.
TextSentencer_T122 18240-18350 Sentence denotes During our preliminary experiments, mice were also sampled and assayed at days 8 and 10 p.i. (data not shown).
TextSentencer_T122 18240-18350 Sentence denotes During our preliminary experiments, mice were also sampled and assayed at days 8 and 10 p.i. (data not shown).
TextSentencer_T123 18351-18452 Sentence denotes However, at these time points only some mice had virus in their CNS, making the results too variable.
TextSentencer_T123 18351-18452 Sentence denotes However, at these time points only some mice had virus in their CNS, making the results too variable.
TextSentencer_T124 18453-18532 Sentence denotes The day 13 p.i. was the first interval when all mice had virus in their brains.
TextSentencer_T124 18453-18532 Sentence denotes The day 13 p.i. was the first interval when all mice had virus in their brains.
TextSentencer_T125 18533-18753 Sentence denotes Significantly increased mRNA levels of TNF-α, IFNγ, IL-1α, IL-1β, IL-2, IL-6, IL-10, MCP-1, RANTES and IP-10 were seen in the TBEV-infected mice of all strains when compared to negative uninfected controls at day 13 p.i.
TextSentencer_T125 18533-18753 Sentence denotes Significantly increased mRNA levels of TNF-α, IFNγ, IL-1α, IL-1β, IL-2, IL-6, IL-10, MCP-1, RANTES and IP-10 were seen in the TBEV-infected mice of all strains when compared to negative uninfected controls at day 13 p.i.
TextSentencer_T126 18754-18986 Sentence denotes In case of CCL3/MIP-1α ( Figure 4D ) and CCL4/MIP-1β ( Figure 4E ) mRNA, only sensitive strains BALB/c and CcS-11 exhibited upregulated expression after the TBEV infection, whilst the expression in infected STS mice was not changed.
TextSentencer_T126 18754-18986 Sentence denotes In case of CCL3/MIP-1α ( Figure 4D ) and CCL4/MIP-1β ( Figure 4E ) mRNA, only sensitive strains BALB/c and CcS-11 exhibited upregulated expression after the TBEV infection, whilst the expression in infected STS mice was not changed.
TextSentencer_T127 18987-19178 Sentence denotes The levels of IL-5 mRNA were increased only in brains of infected CcS-11 mice ( Figure 4J ), but the infection did not affect the expression of this cytokine in brains of BALB/c and STS mice.
TextSentencer_T127 18987-19178 Sentence denotes The levels of IL-5 mRNA were increased only in brains of infected CcS-11 mice ( Figure 4J ), but the infection did not affect the expression of this cytokine in brains of BALB/c and STS mice.
TextSentencer_T128 19179-19321 Sentence denotes The levels of IFN-γ were the highest in brains of infected CcS-11 mice; BALB/c mice exhibited higher levels than STS (p < 0.0005; Figure 4A ).
TextSentencer_T128 19179-19321 Sentence denotes The levels of IFN-γ were the highest in brains of infected CcS-11 mice; BALB/c mice exhibited higher levels than STS (p < 0.0005; Figure 4A ).
TextSentencer_T129 19322-19530 Sentence denotes The levels of upregulation of IL-6 mRNA expression were similar in BALB/c and CcS-11 mice, but both these strains exhibited significantly enhanced expression in comparison to STS mice (p < 0.005; Figure 4K ).
TextSentencer_T129 19322-19530 Sentence denotes The levels of upregulation of IL-6 mRNA expression were similar in BALB/c and CcS-11 mice, but both these strains exhibited significantly enhanced expression in comparison to STS mice (p < 0.005; Figure 4K ).
TextSentencer_T130 19531-19698 Sentence denotes Major differences in the cytokine mRNA expression among the infected BALB/c, CcS-11 and STS mice were seen in case of MCP-1 ( Figure 4C ) and IP-10 ( Figure 4M ) mRNA.
TextSentencer_T130 19531-19698 Sentence denotes Major differences in the cytokine mRNA expression among the infected BALB/c, CcS-11 and STS mice were seen in case of MCP-1 ( Figure 4C ) and IP-10 ( Figure 4M ) mRNA.
TextSentencer_T131 19699-19907 Sentence denotes CcS-11 mice had the highest levels of MCP-1 and IP-10 mRNA in brains, while BALB/c had lower levels of MCP-1 and IP-10 mRNA when compared to CcS-11 mice, but higher when compared to STS mice ( Figure 4C, M) .
TextSentencer_T131 19699-19907 Sentence denotes CcS-11 mice had the highest levels of MCP-1 and IP-10 mRNA in brains, while BALB/c had lower levels of MCP-1 and IP-10 mRNA when compared to CcS-11 mice, but higher when compared to STS mice ( Figure 4C, M) .
TextSentencer_T132 19908-20057 Sentence denotes The dynamics of the changes in cytokine/chemokine mRNA expression was investigated at days 2, 4, 6 and 7 after i.c. inoculation of TBEV ( Figure 5 ).
TextSentencer_T132 19908-20057 Sentence denotes The dynamics of the changes in cytokine/chemokine mRNA expression was investigated at days 2, 4, 6 and 7 after i.c. inoculation of TBEV ( Figure 5 ).
TextSentencer_T133 20058-20178 Sentence denotes No changes in the levels of IL-5 mRNA ( Figure 5I ) were observed in any of the studied mouse strains at any time point.
TextSentencer_T133 20058-20178 Sentence denotes No changes in the levels of IL-5 mRNA ( Figure 5I ) were observed in any of the studied mouse strains at any time point.
TextSentencer_T134 20179-20306 Sentence denotes TNF-α ( Figure 5B ), CCL2/MCP-1 ( Figure 5C ) and CCL4/MIP-1β ( Figure 5D ) mRNA levels increased significantly from day 2 p.i.
TextSentencer_T134 20179-20306 Sentence denotes TNF-α ( Figure 5B ), CCL2/MCP-1 ( Figure 5C ) and CCL4/MIP-1β ( Figure 5D ) mRNA levels increased significantly from day 2 p.i.
TextSentencer_T135 20307-20447 Sentence denotes A significant increase in the level of mRNA for IFN-γ, IL-1β, IL-2, IL-6 and CCL5/ RANTES (Figure 5 A, G, H, J, E) was seen from day 4 p. i.
TextSentencer_T135 20307-20447 Sentence denotes A significant increase in the level of mRNA for IFN-γ, IL-1β, IL-2, IL-6 and CCL5/ RANTES (Figure 5 A, G, H, J, E) was seen from day 4 p. i.
TextSentencer_T136 20448-20519 Sentence denotes Expression of IL-1α mRNA was enhanced from the day 6 p.i. (Figure 5F ).
TextSentencer_T136 20448-20519 Sentence denotes Expression of IL-1α mRNA was enhanced from the day 6 p.i. (Figure 5F ).
TextSentencer_T137 20520-20717 Sentence denotes A large variation in the values of MIP-1α, IL-10 (data not shown) and IL-2 ( Figure 5H ) mRNA was observed between the individual mice within the strain each day after the i.c. inoculation of TBEV.
TextSentencer_T137 20520-20717 Sentence denotes A large variation in the values of MIP-1α, IL-10 (data not shown) and IL-2 ( Figure 5H ) mRNA was observed between the individual mice within the strain each day after the i.c. inoculation of TBEV.
TextSentencer_T138 20718-20819 Sentence denotes IFN-γ mRNA levels were much higher in CcS-11 mice at day 7 p.i. when compared to STS mice (p < 0.05).
TextSentencer_T138 20718-20819 Sentence denotes IFN-γ mRNA levels were much higher in CcS-11 mice at day 7 p.i. when compared to STS mice (p < 0.05).
TextSentencer_T139 20820-21014 Sentence denotes Similarly, the lowest levels of IL-6 (p < 0.0005) and CCL5/RANTES (BALB/c vs. STS, p < 0.05; CcS-11 vs. STS, p < 0.005) mRNA were detected in STS mice versus BALB/c and CcS-11 mice at day 7 p.i.
TextSentencer_T139 20820-21014 Sentence denotes Similarly, the lowest levels of IL-6 (p < 0.0005) and CCL5/RANTES (BALB/c vs. STS, p < 0.05; CcS-11 vs. STS, p < 0.005) mRNA were detected in STS mice versus BALB/c and CcS-11 mice at day 7 p.i.
TextSentencer_T140 21015-21141 Sentence denotes In contrast, STS mice had very enhanced levels of IL-1β mRNA at day 7 p.i. in comparison to BALB/c and CcS-11 mice (p < 0.05).
TextSentencer_T140 21015-21141 Sentence denotes In contrast, STS mice had very enhanced levels of IL-1β mRNA at day 7 p.i. in comparison to BALB/c and CcS-11 mice (p < 0.05).
TextSentencer_T141 21142-21256 Sentence denotes The greatest differences among the infected BALB/c, CcS-11 and STS mice were seen in case of MCP-1 and IP-10 mRNA.
TextSentencer_T141 21142-21256 Sentence denotes The greatest differences among the infected BALB/c, CcS-11 and STS mice were seen in case of MCP-1 and IP-10 mRNA.
TextSentencer_T142 21257-21436 Sentence denotes CcS-11 mice had the highest levels of MCP-1 mRNA in brains at days 4, 6 (p < 0.05) and 7 p.i. (BALB/c vs. STS, p < 0.005; CcS-11 vs. BALB/c, p < 0.05; CcS-11 vs. STS, p < 0.0005).
TextSentencer_T142 21257-21436 Sentence denotes CcS-11 mice had the highest levels of MCP-1 mRNA in brains at days 4, 6 (p < 0.05) and 7 p.i. (BALB/c vs. STS, p < 0.005; CcS-11 vs. BALB/c, p < 0.05; CcS-11 vs. STS, p < 0.0005).
TextSentencer_T143 21437-21716 Sentence denotes The levels of IP-10 mRNA were the highest in CcS-11 mice at all investigated time points p.i., the highest differences being observed at day 6 p.i. (BALB/c vs. CcS-11 and STS vs. CcS-11, p < 0.005) and at day 7 p.i. (BALB/c vs. CcS-11, p < 0.005, and STS vs. CcS-11, p < 0.0005).
TextSentencer_T143 21437-21716 Sentence denotes The levels of IP-10 mRNA were the highest in CcS-11 mice at all investigated time points p.i., the highest differences being observed at day 6 p.i. (BALB/c vs. CcS-11 and STS vs. CcS-11, p < 0.005) and at day 7 p.i. (BALB/c vs. CcS-11, p < 0.005, and STS vs. CcS-11, p < 0.0005).
TextSentencer_T144 21717-21820 Sentence denotes BALB/c had lower levels of IP-10 mRNA than CcS-11 mice (p < 0.05), but higher than STS mice (p < 0.05).
TextSentencer_T144 21717-21820 Sentence denotes BALB/c had lower levels of IP-10 mRNA than CcS-11 mice (p < 0.05), but higher than STS mice (p < 0.05).
TextSentencer_T145 21821-21948 Sentence denotes A correlation between the IP-10 mRNA levels with the sensitivity of mice to the TBEV infection was observed (Figures 1C, 5K) .
TextSentencer_T145 21821-21948 Sentence denotes A correlation between the IP-10 mRNA levels with the sensitivity of mice to the TBEV infection was observed (Figures 1C, 5K) .
TextSentencer_T146 21949-22046 Sentence denotes No changes in the expression of IL-4 mRNA were seen in any mouse strain after either s.c. or i.c.
TextSentencer_T146 21949-22046 Sentence denotes No changes in the expression of IL-4 mRNA were seen in any mouse strain after either s.c. or i.c.
TextSentencer_T147 22047-22081 Sentence denotes TBEV inoculation (data not shown).
TextSentencer_T147 22047-22081 Sentence denotes TBEV inoculation (data not shown).
TextSentencer_T148 22082-22279 Sentence denotes In order to compare the host's humoral immune response in the infected BALB/c, CcS-11 and STS mice after s.c. inoculation of TBEV, TBEV-specific antibodies were tested at days 5, 8, 10 and 13 p.i..
TextSentencer_T148 22082-22279 Sentence denotes In order to compare the host's humoral immune response in the infected BALB/c, CcS-11 and STS mice after s.c. inoculation of TBEV, TBEV-specific antibodies were tested at days 5, 8, 10 and 13 p.i..
TextSentencer_T149 22280-22385 Sentence denotes The titer of neutralizing antibodies was determined by PRNT (plaque reduction neutralization test) assay.
TextSentencer_T149 22280-22385 Sentence denotes The titer of neutralizing antibodies was determined by PRNT (plaque reduction neutralization test) assay.
TextSentencer_T150 22386-22514 Sentence denotes Before day 10, a very low titer of neutralizing antibodies and no difference between the strains were observed (data not shown).
TextSentencer_T150 22386-22514 Sentence denotes Before day 10, a very low titer of neutralizing antibodies and no difference between the strains were observed (data not shown).
TextSentencer_T151 22515-22702 Sentence denotes At day 10 p.i., very low titers of neutralizing antibodies were found in serum of BALB/c and CcS-11 mice (less than 1:20), but STS mice exhibited neutralizing titers of 1:100 (p < 0.005).
TextSentencer_T151 22515-22702 Sentence denotes At day 10 p.i., very low titers of neutralizing antibodies were found in serum of BALB/c and CcS-11 mice (less than 1:20), but STS mice exhibited neutralizing titers of 1:100 (p < 0.005).
TextSentencer_T152 22703-22795 Sentence denotes At day 13 p.i., no increase in the titer of neutralizing antibodies was seen in CcS-11 mice.
TextSentencer_T152 22703-22795 Sentence denotes At day 13 p.i., no increase in the titer of neutralizing antibodies was seen in CcS-11 mice.
TextSentencer_T153 22796-22913 Sentence denotes BALB/c mice exhibited neutralizing titers of 1:100, but STS mice had titers reaching 1:640 (p < 0.0005) ( Figure 6 ).
TextSentencer_T153 22796-22913 Sentence denotes BALB/c mice exhibited neutralizing titers of 1:100, but STS mice had titers reaching 1:640 (p < 0.0005) ( Figure 6 ).
TextSentencer_T154 22914-22989 Sentence denotes No neutralizing activity was detected in sera from control uninfected mice.
TextSentencer_T154 22914-22989 Sentence denotes No neutralizing activity was detected in sera from control uninfected mice.
TextSentencer_T155 22990-23146 Sentence denotes Mice provide a useful tool for study of human TBE, since they recapitulate the pathological and pathophysiological processes seen in severe human TBE cases.
TextSentencer_T155 22990-23146 Sentence denotes Mice provide a useful tool for study of human TBE, since they recapitulate the pathological and pathophysiological processes seen in severe human TBE cases.
TextSentencer_T156 23147-23266 Sentence denotes However, biological and virological markers indicating the severity of TBE in mice as well as in humans remain unclear.
TextSentencer_T156 23147-23266 Sentence denotes However, biological and virological markers indicating the severity of TBE in mice as well as in humans remain unclear.
TextSentencer_T157 23267-23497 Sentence denotes The severity of TBE can be influenced by a variety of factors, e.g., the inoculation dose and virulence of the virus [1] , the age, sex and immune status of the host [2] , and susceptibility based on the host's genetic background.
TextSentencer_T157 23267-23497 Sentence denotes The severity of TBE can be influenced by a variety of factors, e.g., the inoculation dose and virulence of the virus [1] , the age, sex and immune status of the host [2] , and susceptibility based on the host's genetic background.
TextSentencer_T158 23498-23622 Sentence denotes Generally, age of the host is the most common host risk factor identified for severe forms of flavivirus encephalitis [29] .
TextSentencer_T158 23498-23622 Sentence denotes Generally, age of the host is the most common host risk factor identified for severe forms of flavivirus encephalitis [29] .
TextSentencer_T159 23623-23751 Sentence denotes However, genetic host risk factors play an important role in the development of severe flaviviral neurological diseases as well.
TextSentencer_T159 23623-23751 Sentence denotes However, genetic host risk factors play an important role in the development of severe flaviviral neurological diseases as well.
TextSentencer_T160 23752-23862 Sentence denotes Several genetic host factors associated with the severe forms of flavivirus encephalitis have been identified.
TextSentencer_T160 23752-23862 Sentence denotes Several genetic host factors associated with the severe forms of flavivirus encephalitis have been identified.
TextSentencer_T161 23863-24120 Sentence denotes These include polymorphisms in HLA-A and HLA-B, polymorphism located in the promoter region of the human CD209 gene [7] and functional Toll-like receptor 3 gene [4] , deletion in CCR5 [5] and variability in 2´-5´-oligoadenylate synthetase gene cluster [6] .
TextSentencer_T161 23863-24120 Sentence denotes These include polymorphisms in HLA-A and HLA-B, polymorphism located in the promoter region of the human CD209 gene [7] and functional Toll-like receptor 3 gene [4] , deletion in CCR5 [5] and variability in 2´-5´-oligoadenylate synthetase gene cluster [6] .
TextSentencer_T162 24121-24259 Sentence denotes In our study, we developed a new mouse model of hosts differing in the susceptibility to TBEV infection based on CcS/Dem RC mouse strains.
TextSentencer_T162 24121-24259 Sentence denotes In our study, we developed a new mouse model of hosts differing in the susceptibility to TBEV infection based on CcS/Dem RC mouse strains.
TextSentencer_T163 24260-24375 Sentence denotes We observed clearly different patterns in the susceptibility of the CcS/Dem RC strains to s.c. infection with TBEV.
TextSentencer_T163 24260-24375 Sentence denotes We observed clearly different patterns in the susceptibility of the CcS/Dem RC strains to s.c. infection with TBEV.
TextSentencer_T164 24376-24598 Sentence denotes Out of the eight strains tested, one (STS) exhibited low susceptibility, five intermediate susceptibility (CcS-3, CcS-7, CcS-9, CcS-16 and BALB/c) and two strains (CcS-11 and CcS-15) high susceptibility (Additional file 1:
TextSentencer_T164 24376-24598 Sentence denotes Out of the eight strains tested, one (STS) exhibited low susceptibility, five intermediate susceptibility (CcS-3, CcS-7, CcS-9, CcS-16 and BALB/c) and two strains (CcS-11 and CcS-15) high susceptibility (Additional file 1:
TextSentencer_T165 24599-24611 Sentence denotes Figure S1 ).
TextSentencer_T165 24599-24611 Sentence denotes Figure S1 ).
TextSentencer_T166 24612-24841 Sentence denotes Differences in MST between the strains CcS-11, BALB/c and STS were also observed after i.c. inoculation of TBEV, i.e., CcS-11 mice had the shortest MST, BALB/c medium MST and STS the longest MST and higher survival ( Figure 1C ).
TextSentencer_T166 24612-24841 Sentence denotes Differences in MST between the strains CcS-11, BALB/c and STS were also observed after i.c. inoculation of TBEV, i.e., CcS-11 mice had the shortest MST, BALB/c medium MST and STS the longest MST and higher survival ( Figure 1C ).
TextSentencer_T167 24842-24911 Sentence denotes These differences indicate the presence of TBEV susceptibility genes.
TextSentencer_T167 24842-24911 Sentence denotes These differences indicate the presence of TBEV susceptibility genes.
TextSentencer_T168 24912-25083 Sentence denotes Different susceptibility to virus infection in recombinant inbred strains between BALB/c and STS mice was also observed in case of infection with murine coronavirus [30] .
TextSentencer_T168 24912-25083 Sentence denotes Different susceptibility to virus infection in recombinant inbred strains between BALB/c and STS mice was also observed in case of infection with murine coronavirus [30] .
TextSentencer_T169 25084-25345 Sentence denotes After i.c. inoculation of 100 pfu of murine coronavirus, all BALB/c mice were highly susceptible and died; in contrast, STS mice were shown to be partially resistant, with a mortality rate of 30%, longer survival times and lower rates of virus production [30] .
TextSentencer_T169 25084-25345 Sentence denotes After i.c. inoculation of 100 pfu of murine coronavirus, all BALB/c mice were highly susceptible and died; in contrast, STS mice were shown to be partially resistant, with a mortality rate of 30%, longer survival times and lower rates of virus production [30] .
TextSentencer_T170 25346-25571 Sentence denotes In our study, RC strain CcS-11, which contains approximately 12.5% genes of the donor strain STS and 87.5% genes of the background strain BALB/c, was more sensitive to TBEV infection than both parental strains BALB/c and STS.
TextSentencer_T170 25346-25571 Sentence denotes In our study, RC strain CcS-11, which contains approximately 12.5% genes of the donor strain STS and 87.5% genes of the background strain BALB/c, was more sensitive to TBEV infection than both parental strains BALB/c and STS.
TextSentencer_T171 25572-25726 Sentence denotes The observations of progeny having a phenotype beyond the range of the phenotype of its parents are not rare in traits controlled by multiple genes [18] .
TextSentencer_T171 25572-25726 Sentence denotes The observations of progeny having a phenotype beyond the range of the phenotype of its parents are not rare in traits controlled by multiple genes [18] .
TextSentencer_T172 25727-25991 Sentence denotes Such an observation may be due to multiple gene-gene interactions of quantitative trait loci, which in new combinations of these genes in RC or chromosomal substitution can lead to the appearance of new phenotypes that exceed their range in parental strains [18] .
TextSentencer_T172 25727-25991 Sentence denotes Such an observation may be due to multiple gene-gene interactions of quantitative trait loci, which in new combinations of these genes in RC or chromosomal substitution can lead to the appearance of new phenotypes that exceed their range in parental strains [18] .
TextSentencer_T173 25992-26094 Sentence denotes Another possibility is when some progeny receives predominantly susceptible alleles from both parents.
TextSentencer_T173 25992-26094 Sentence denotes Another possibility is when some progeny receives predominantly susceptible alleles from both parents.
TextSentencer_T174 26095-26448 Sentence denotes These susceptible alleles are distinct from genes H2, Cd209, Tlr3, Ccr5 and Oas1b, which are involved in genetic control of susceptibility to flavivirus encephalitis (see above), because these genes are in CcS-11 localized on segments derived from the background BALB/c strain [ Figure 1A and Mouse Genome Informatics (http://www.informatics.jax.org/)].
TextSentencer_T174 26095-26448 Sentence denotes These susceptible alleles are distinct from genes H2, Cd209, Tlr3, Ccr5 and Oas1b, which are involved in genetic control of susceptibility to flavivirus encephalitis (see above), because these genes are in CcS-11 localized on segments derived from the background BALB/c strain [ Figure 1A and Mouse Genome Informatics (http://www.informatics.jax.org/)].
TextSentencer_T175 26449-26581 Sentence denotes We also cannot exclude the possibility of a spontaneous mutation appearing during inbreeding and causing the unique phenotype [18] .
TextSentencer_T175 26449-26581 Sentence denotes We also cannot exclude the possibility of a spontaneous mutation appearing during inbreeding and causing the unique phenotype [18] .
TextSentencer_T176 26582-26753 Sentence denotes Similarly to our study, CcS-11 mice were more susceptible to infection with Leishmania tropica [18] and to Trypanosoma brucei brucei [31] than both parental mouse strains.
TextSentencer_T176 26582-26753 Sentence denotes Similarly to our study, CcS-11 mice were more susceptible to infection with Leishmania tropica [18] and to Trypanosoma brucei brucei [31] than both parental mouse strains.
TextSentencer_T177 26754-26818 Sentence denotes However, CcS-11 is more resistant to L. major than BALB/c [32] .
TextSentencer_T177 26754-26818 Sentence denotes However, CcS-11 is more resistant to L. major than BALB/c [32] .
TextSentencer_T178 26819-27034 Sentence denotes We attempted to identify biological markers that could be related to differences in survival rates of the highly susceptible (CcS-11), medium susceptible (BALB/c) and lowly susceptible (STS) mice infected with TBEV.
TextSentencer_T178 26819-27034 Sentence denotes We attempted to identify biological markers that could be related to differences in survival rates of the highly susceptible (CcS-11), medium susceptible (BALB/c) and lowly susceptible (STS) mice infected with TBEV.
TextSentencer_T179 27035-27142 Sentence denotes STS mice had very low and delayed viremia when compared with BALB/c and CcS-11 mice after s.c. inoculation.
TextSentencer_T179 27035-27142 Sentence denotes STS mice had very low and delayed viremia when compared with BALB/c and CcS-11 mice after s.c. inoculation.
TextSentencer_T180 27143-27299 Sentence denotes All mice showed brain infection, but lower titers were detected in brains of STS mice, while BALB/c and CcS-11 mice showed higher titers for 3-4 log 10 pfu.
TextSentencer_T180 27143-27299 Sentence denotes All mice showed brain infection, but lower titers were detected in brains of STS mice, while BALB/c and CcS-11 mice showed higher titers for 3-4 log 10 pfu.
TextSentencer_T181 27300-27430 Sentence denotes This indicated lower replication rates of the virus in STS mice, but no difference in replication rates in BALB/c and CcS-11 mice.
TextSentencer_T181 27300-27430 Sentence denotes This indicated lower replication rates of the virus in STS mice, but no difference in replication rates in BALB/c and CcS-11 mice.
TextSentencer_T182 27431-27582 Sentence denotes To avoid virus-host interactions before virus neuroinvasion, mice were inoculated i.c., and the dynamics of virus growth in the brain was investigated.
TextSentencer_T182 27431-27582 Sentence denotes To avoid virus-host interactions before virus neuroinvasion, mice were inoculated i.c., and the dynamics of virus growth in the brain was investigated.
TextSentencer_T183 27583-27776 Sentence denotes Although BALB/c, CcS-11 and STS mice showed different MST after i.c. inoculation, almost the same virus titers were observed in all investigated mouse strains at all intervals p.i. (Figure 2 ).
TextSentencer_T183 27583-27776 Sentence denotes Although BALB/c, CcS-11 and STS mice showed different MST after i.c. inoculation, almost the same virus titers were observed in all investigated mouse strains at all intervals p.i. (Figure 2 ).
TextSentencer_T184 27777-27863 Sentence denotes Virus replication rate is not, therefore, the main factor influencing MST of the host.
TextSentencer_T184 27777-27863 Sentence denotes Virus replication rate is not, therefore, the main factor influencing MST of the host.
TextSentencer_T185 27864-28079 Sentence denotes Similarly, no differences in tissue tropism, viral load or kinetics were observed during acute West Nile virus infection in mouse strains C57BL/6 and C3H/HeN with higher and lower survival rates, respectively [33] .
TextSentencer_T185 27864-28079 Sentence denotes Similarly, no differences in tissue tropism, viral load or kinetics were observed during acute West Nile virus infection in mouse strains C57BL/6 and C3H/HeN with higher and lower survival rates, respectively [33] .
TextSentencer_T186 28080-28443 Sentence denotes Higher mRNA levels of cell surface marker of B-cells were seen in brains of the mice less susceptible to TBEV infection Mice differing in susceptibility to TBEV infection exhibited some differences in immune cells accumulation in brains during the development of encephalitis as demonstrated by quantification of mRNA of cell-specific markers by real-time RT-PCR.
TextSentencer_T186 28080-28443 Sentence denotes Higher mRNA levels of cell surface marker of B-cells were seen in brains of the mice less susceptible to TBEV infection Mice differing in susceptibility to TBEV infection exhibited some differences in immune cells accumulation in brains during the development of encephalitis as demonstrated by quantification of mRNA of cell-specific markers by real-time RT-PCR.
TextSentencer_T187 28444-28653 Sentence denotes In our previous work using BALB/c, SCID on the BALB/c background, C57BL/6 and C57BL/6 Cd8−/− mice we reported that CD8 + T-cells have a dual role and mediate recovery, but also immunopathology during TBE [2] .
TextSentencer_T187 28444-28653 Sentence denotes In our previous work using BALB/c, SCID on the BALB/c background, C57BL/6 and C57BL/6 Cd8−/− mice we reported that CD8 + T-cells have a dual role and mediate recovery, but also immunopathology during TBE [2] .
TextSentencer_T188 28654-28782 Sentence denotes In this study, no differences in the level of CD8 mRNA were seen between the BALB/c, CcS-11 and STS mice after s.c. inoculation.
TextSentencer_T188 28654-28782 Sentence denotes In this study, no differences in the level of CD8 mRNA were seen between the BALB/c, CcS-11 and STS mice after s.c. inoculation.
TextSentencer_T189 28783-28971 Sentence denotes After i.c. inoculation, only STS mice exhibited slightly higher levels of CD8 mRNA (but also CD4 mRNA) than BALB/c mice at day 6 p.i., but no other differences were observed ( Figure 3B ).
TextSentencer_T189 28783-28971 Sentence denotes After i.c. inoculation, only STS mice exhibited slightly higher levels of CD8 mRNA (but also CD4 mRNA) than BALB/c mice at day 6 p.i., but no other differences were observed ( Figure 3B ).
TextSentencer_T190 28972-29076 Sentence denotes The most interesting results provided quantification of mRNA for CD19, a cell surface marker of B-cells.
TextSentencer_T190 28972-29076 Sentence denotes The most interesting results provided quantification of mRNA for CD19, a cell surface marker of B-cells.
TextSentencer_T191 29077-29159 Sentence denotes No increase of CD19 mRNA was observed after i.c. inoculation in all mouse strains.
TextSentencer_T191 29077-29159 Sentence denotes No increase of CD19 mRNA was observed after i.c. inoculation in all mouse strains.
TextSentencer_T192 29160-29332 Sentence denotes After s.c. inoculation, strains BALB/c and CcS-11 did not increase the levels of CD19 mRNA in their brains, whereas STS mice exhibited a significant increase ( Figure 3A ).
TextSentencer_T192 29160-29332 Sentence denotes After s.c. inoculation, strains BALB/c and CcS-11 did not increase the levels of CD19 mRNA in their brains, whereas STS mice exhibited a significant increase ( Figure 3A ).
TextSentencer_T193 29333-29421 Sentence denotes This might indicate stronger B cell infiltration in brains of the less susceptible mice.
TextSentencer_T193 29333-29421 Sentence denotes This might indicate stronger B cell infiltration in brains of the less susceptible mice.
TextSentencer_T194 29422-29563 Sentence denotes B cells were also observed in brains in some studies focused on flavivirus encephalitis [34] , predominantly found in the perivascular space.
TextSentencer_T194 29422-29563 Sentence denotes B cells were also observed in brains in some studies focused on flavivirus encephalitis [34] , predominantly found in the perivascular space.
TextSentencer_T195 29564-29666 Sentence denotes The proportion of B and T cells in the brain may vary depending on the infecting flavivirus [35, 36] .
TextSentencer_T195 29564-29666 Sentence denotes The proportion of B and T cells in the brain may vary depending on the infecting flavivirus [35, 36] .
TextSentencer_T196 29667-29813 Sentence denotes It is known that TBEV, unlike to Japanese encephalitis and West Nile virus infections, induces CXCL13, a B-cell chemoattractant, in the CNS [37] .
TextSentencer_T196 29667-29813 Sentence denotes It is known that TBEV, unlike to Japanese encephalitis and West Nile virus infections, induces CXCL13, a B-cell chemoattractant, in the CNS [37] .
TextSentencer_T197 29814-29985 Sentence denotes Although the antibody reaction is clearly important systemically [38] , the importance of B cells infiltrating brain parenchyma in confining of the infection is not clear.
TextSentencer_T197 29814-29985 Sentence denotes Although the antibody reaction is clearly important systemically [38] , the importance of B cells infiltrating brain parenchyma in confining of the infection is not clear.
TextSentencer_T198 29986-30254 Sentence denotes More severe form of TBE associated with higher expression of proinflammatory cytokines/chemokines in the brain Accumulation of cytokines and chemokines in the CNS may accentuate progression of encephalitis instead of restricting viral replication [37, [39] [40] [41] .
TextSentencer_T198 29986-30254 Sentence denotes More severe form of TBE associated with higher expression of proinflammatory cytokines/chemokines in the brain Accumulation of cytokines and chemokines in the CNS may accentuate progression of encephalitis instead of restricting viral replication [37, [39] [40] [41] .
TextSentencer_T199 30255-30403 Sentence denotes Deregulated or excess release of proinflammatory mediators by the brain may induce tissue damage with different pathology and disease outcome [42] .
TextSentencer_T199 30255-30403 Sentence denotes Deregulated or excess release of proinflammatory mediators by the brain may induce tissue damage with different pathology and disease outcome [42] .
TextSentencer_T200 30404-30551 Sentence denotes In this study, we examined the cytokine/chemokine response in brains of the mice differing in susceptibility to TBEV infection (Figures 4 and 5) .
TextSentencer_T200 30404-30551 Sentence denotes In this study, we examined the cytokine/chemokine response in brains of the mice differing in susceptibility to TBEV infection (Figures 4 and 5) .
TextSentencer_T201 30552-30763 Sentence denotes We showed that a wide range of cytokine and chemokine mRNAs for TNF-α, IFNγ, IL-1α, IL-1β, IL-2, IL-6, IL-10, CCL2/MCP-1, CCL5/RANTES, IP-10, MIP-1α, MIP-1β and others was produced in response to TBEV infection.
TextSentencer_T201 30552-30763 Sentence denotes We showed that a wide range of cytokine and chemokine mRNAs for TNF-α, IFNγ, IL-1α, IL-1β, IL-2, IL-6, IL-10, CCL2/MCP-1, CCL5/RANTES, IP-10, MIP-1α, MIP-1β and others was produced in response to TBEV infection.
TextSentencer_T202 30764-30883 Sentence denotes There was no clear correlation between the peak of cytokine/chemokine production and the increase of TBEV in the brain.
TextSentencer_T202 30764-30883 Sentence denotes There was no clear correlation between the peak of cytokine/chemokine production and the increase of TBEV in the brain.
TextSentencer_T203 30884-31050 Sentence denotes After i.c. inoculation, all mice had comparable virus titers in the CNS ( Figure 2C ), but the levels of cytokine/chemokine expression differed markedly ( Figure 5 ).
TextSentencer_T203 30884-31050 Sentence denotes After i.c. inoculation, all mice had comparable virus titers in the CNS ( Figure 2C ), but the levels of cytokine/chemokine expression differed markedly ( Figure 5 ).
TextSentencer_T204 31051-31107 Sentence denotes STS mice had the highest levels of IL-1β mRNA after i.c.
TextSentencer_T204 31051-31107 Sentence denotes STS mice had the highest levels of IL-1β mRNA after i.c.
TextSentencer_T205 31108-31164 Sentence denotes TBEV inoculation when compared to other strains of mice.
TextSentencer_T205 31108-31164 Sentence denotes TBEV inoculation when compared to other strains of mice.
TextSentencer_T206 31165-31277 Sentence denotes In contrast, it is known that higher levels of IL-1β are associated with more severe cases of chikungunya [43] .
TextSentencer_T206 31165-31277 Sentence denotes In contrast, it is known that higher levels of IL-1β are associated with more severe cases of chikungunya [43] .
TextSentencer_T207 31278-31405 Sentence denotes Most of other cytokine/ chemokine mRNAs tested were on the lowest level in STS mice in comparison to CcS-11 and/or BALB/c mice.
TextSentencer_T207 31278-31405 Sentence denotes Most of other cytokine/ chemokine mRNAs tested were on the lowest level in STS mice in comparison to CcS-11 and/or BALB/c mice.
TextSentencer_T208 31406-31721 Sentence denotes The highest levels of proinflammatory cytokines/ chemokines (IFNγ, CCL3/MIP-1α, CCL2/MCP-1, IP-10) (after s.c. and i.c. inoculation) and IL-5 (after s.c. inoculation) were detected in CcS-11 mice, indicating that these cytokines/chemokines can be associated with a more severe form of TBE in our experimental model.
TextSentencer_T208 31406-31721 Sentence denotes The highest levels of proinflammatory cytokines/ chemokines (IFNγ, CCL3/MIP-1α, CCL2/MCP-1, IP-10) (after s.c. and i.c. inoculation) and IL-5 (after s.c. inoculation) were detected in CcS-11 mice, indicating that these cytokines/chemokines can be associated with a more severe form of TBE in our experimental model.
TextSentencer_T209 31722-31859 Sentence denotes On the other hand, the lowest levels of IL-6 and CCL5/ RANTES, and also CCL3/MIP-1α and CCL4/MIP-1β mRNAs, were demonstrated in STS mice.
TextSentencer_T209 31722-31859 Sentence denotes On the other hand, the lowest levels of IL-6 and CCL5/ RANTES, and also CCL3/MIP-1α and CCL4/MIP-1β mRNAs, were demonstrated in STS mice.
TextSentencer_T210 31860-32013 Sentence denotes These data support the theory that excessive production of proinflammatory mediators could contribute to development of more severe or acute form of TBE.
TextSentencer_T210 31860-32013 Sentence denotes These data support the theory that excessive production of proinflammatory mediators could contribute to development of more severe or acute form of TBE.
TextSentencer_T211 32014-32229 Sentence denotes Similarly to our study, higher levels of CCL5/RANTES, CCL3/MIP-1α, CCL4/MIP-1β and IP-10 mRNA were found to be associated with a lethal form of West Nile virus infection in comparison with the non-lethal form [41] .
TextSentencer_T211 32014-32229 Sentence denotes Similarly to our study, higher levels of CCL5/RANTES, CCL3/MIP-1α, CCL4/MIP-1β and IP-10 mRNA were found to be associated with a lethal form of West Nile virus infection in comparison with the non-lethal form [41] .
TextSentencer_T212 32230-32419 Sentence denotes CCL2/ MCP-1 and IP-10 mRNA levels correlated well with the susceptibility of the mouse strains to TBEV infection, i.e., CcS-11 mice had the highest levels, BALB/c medium and STS the lowest.
TextSentencer_T212 32230-32419 Sentence denotes CCL2/ MCP-1 and IP-10 mRNA levels correlated well with the susceptibility of the mouse strains to TBEV infection, i.e., CcS-11 mice had the highest levels, BALB/c medium and STS the lowest.
TextSentencer_T213 32420-32477 Sentence denotes These data were confirmed in two independent experiments.
TextSentencer_T213 32420-32477 Sentence denotes These data were confirmed in two independent experiments.
TextSentencer_T214 32478-32557 Sentence denotes Both these chemokines can have an important role in immunopathology during TBE.
TextSentencer_T214 32478-32557 Sentence denotes Both these chemokines can have an important role in immunopathology during TBE.
TextSentencer_T215 32558-32690 Sentence denotes It has been demonstrated that neutralization of CCL2/MCP-1 leads to increased survival rates in West Nile virus-infected mice [44] .
TextSentencer_T215 32558-32690 Sentence denotes It has been demonstrated that neutralization of CCL2/MCP-1 leads to increased survival rates in West Nile virus-infected mice [44] .
TextSentencer_T216 32691-32784 Sentence denotes Expression of IP-10 mRNA exhibited the biggest differences between the studied mouse strains.
TextSentencer_T216 32691-32784 Sentence denotes Expression of IP-10 mRNA exhibited the biggest differences between the studied mouse strains.
TextSentencer_T217 32785-32944 Sentence denotes The chemokine IP-10, which is IFN-γ inducible and has the ability to attract activated T cells in the CNS, has also been shown to be a potent neurotoxin [45] .
TextSentencer_T217 32785-32944 Sentence denotes The chemokine IP-10, which is IFN-γ inducible and has the ability to attract activated T cells in the CNS, has also been shown to be a potent neurotoxin [45] .
TextSentencer_T218 32945-33043 Sentence denotes In human TBE patients, IP-10 can be detected in serum as well as in cerebrospinal fluid [46, 47] .
TextSentencer_T218 32945-33043 Sentence denotes In human TBE patients, IP-10 can be detected in serum as well as in cerebrospinal fluid [46, 47] .
TextSentencer_T219 33044-33262 Sentence denotes Using genetically deficient mice and antibody neutralization approaches, it was demonstrated that IP-10 is critical for the recruitment of T-cells into the CNS and survival from West Nile virus infection in mice [48] .
TextSentencer_T219 33044-33262 Sentence denotes Using genetically deficient mice and antibody neutralization approaches, it was demonstrated that IP-10 is critical for the recruitment of T-cells into the CNS and survival from West Nile virus infection in mice [48] .
TextSentencer_T220 33263-33348 Sentence denotes However, excessively high levels of IP-10 in the CNS can be very harmful to the host.
TextSentencer_T220 33263-33348 Sentence denotes However, excessively high levels of IP-10 in the CNS can be very harmful to the host.
TextSentencer_T221 33349-33450 Sentence denotes IP-10 levels in the CNS of HIV-1 -infected individuals correlate positively with disease progression.
TextSentencer_T221 33349-33450 Sentence denotes IP-10 levels in the CNS of HIV-1 -infected individuals correlate positively with disease progression.
TextSentencer_T222 33451-33687 Sentence denotes There is also evidence that IP-10 participates in the neuropathogenesis of SHIV-infected macaques [49, 50] by contributing to the degeneration of neurons possibly through the activation of a calciumdependent apoptotic pathway [45, 51] .
TextSentencer_T222 33451-33687 Sentence denotes There is also evidence that IP-10 participates in the neuropathogenesis of SHIV-infected macaques [49, 50] by contributing to the degeneration of neurons possibly through the activation of a calciumdependent apoptotic pathway [45, 51] .
TextSentencer_T223 33688-33803 Sentence denotes Our data strongly suggest that higher levels of IP-10 in the CNS might be associated with more severe forms of TBE.
TextSentencer_T223 33688-33803 Sentence denotes Our data strongly suggest that higher levels of IP-10 in the CNS might be associated with more severe forms of TBE.
TextSentencer_T224 33804-33952 Sentence denotes Further studies using mice specifically knocked out for one of the genes identified will determine their contribution to host susceptibility to TBE.
TextSentencer_T224 33804-33952 Sentence denotes Further studies using mice specifically knocked out for one of the genes identified will determine their contribution to host susceptibility to TBE.
TextSentencer_T225 33953-34079 Sentence denotes Whether the profile of the chemokine production in human cases of TBE will predict the disease outcome requires further study.
TextSentencer_T225 33953-34079 Sentence denotes Whether the profile of the chemokine production in human cases of TBE will predict the disease outcome requires further study.
TextSentencer_T226 34080-34180 Sentence denotes The importance of neutralizing antibodies in the prevention of flaviviral diseases is well accepted.
TextSentencer_T226 34080-34180 Sentence denotes The importance of neutralizing antibodies in the prevention of flaviviral diseases is well accepted.
TextSentencer_T227 34181-34328 Sentence denotes As a rule, the antibodies with relatively high affinity and avidity to the surface proteins of TBEV virions can be detected in neutralization test.
TextSentencer_T227 34181-34328 Sentence denotes As a rule, the antibodies with relatively high affinity and avidity to the surface proteins of TBEV virions can be detected in neutralization test.
TextSentencer_T228 34329-34442 Sentence denotes Only such antibodies interfere with the interaction of the virus with receptors, preventing it to enter the cell.
TextSentencer_T228 34329-34442 Sentence denotes Only such antibodies interfere with the interaction of the virus with receptors, preventing it to enter the cell.
TextSentencer_T229 34443-34579 Sentence denotes TBEV infection is associated with breakdown of the host blood-brain barrier [26] ; therefore, the antibodies can penetrate into the CNS.
TextSentencer_T229 34443-34579 Sentence denotes TBEV infection is associated with breakdown of the host blood-brain barrier [26] ; therefore, the antibodies can penetrate into the CNS.
TextSentencer_T230 34580-34795 Sentence denotes In our study, STS mice had a strong neutralizing antibody response, CcS-11 mice failed to produce neutralizing antibodies, and BALB/ c mice developed neutralizing antibodies but later and at low titers ( Figure 6 ).
TextSentencer_T230 34580-34795 Sentence denotes In our study, STS mice had a strong neutralizing antibody response, CcS-11 mice failed to produce neutralizing antibodies, and BALB/ c mice developed neutralizing antibodies but later and at low titers ( Figure 6 ).
TextSentencer_T231 34796-34919 Sentence denotes Therefore, our data on TBE support the importance of neutralizing antibodies in preventing neuroinvasion and host fatality.
TextSentencer_T231 34796-34919 Sentence denotes Therefore, our data on TBE support the importance of neutralizing antibodies in preventing neuroinvasion and host fatality.
TextSentencer_T232 34920-35095 Sentence denotes Similar data were obtained in experiments with the mouse strains C3H/HeN and DBA/2 with higher and lower susceptibility to the Japanese encephalitis virus, respectively [40] .
TextSentencer_T232 34920-35095 Sentence denotes Similar data were obtained in experiments with the mouse strains C3H/HeN and DBA/2 with higher and lower susceptibility to the Japanese encephalitis virus, respectively [40] .
TextSentencer_T233 35096-35231 Sentence denotes In human TBE patients, those who fail to produce TBEV neutralizing antibodies usually have a very severe course of the infection [52] .
TextSentencer_T233 35096-35231 Sentence denotes In human TBE patients, those who fail to produce TBEV neutralizing antibodies usually have a very severe course of the infection [52] .
TextSentencer_T234 35232-35390 Sentence denotes The same is seen in patients who receive vaccination against TBEV and develop antibody response, but their antibodies do not have neutralizing capacity [52] .
TextSentencer_T234 35232-35390 Sentence denotes The same is seen in patients who receive vaccination against TBEV and develop antibody response, but their antibodies do not have neutralizing capacity [52] .
TextSentencer_T235 35391-35576 Sentence denotes In summary, our experimental model showed that earlier and greater amounts of neutralizing antibodies could limit neuroinvasion of TBEV and disease progression in less susceptible mice.
TextSentencer_T235 35391-35576 Sentence denotes In summary, our experimental model showed that earlier and greater amounts of neutralizing antibodies could limit neuroinvasion of TBEV and disease progression in less susceptible mice.
TextSentencer_T236 35577-35842 Sentence denotes Moreover, we described that resistant mice exhibit stronger B-cell infiltration (as measured by quantification of changes in mRNA levels of cell surface markers) but lower cytokine/chemokine production in the CNS when compared to the more susceptible mouse strains.
TextSentencer_T236 35577-35842 Sentence denotes Moreover, we described that resistant mice exhibit stronger B-cell infiltration (as measured by quantification of changes in mRNA levels of cell surface markers) but lower cytokine/chemokine production in the CNS when compared to the more susceptible mouse strains.
TextSentencer_T237 35843-36136 Sentence denotes The most susceptible mice have the highest overall cytokine/chemokine production in the CNS, particularly of CCL2/MCP-1 and IP-10, which can elevate the primarily proinflammatory environment in the brain, which could result in brain tissue damage and death of the host through immunopathology.
TextSentencer_T237 35843-36136 Sentence denotes The most susceptible mice have the highest overall cytokine/chemokine production in the CNS, particularly of CCL2/MCP-1 and IP-10, which can elevate the primarily proinflammatory environment in the brain, which could result in brain tissue damage and death of the host through immunopathology.
TextSentencer_T238 36137-36230 Sentence denotes This suggests an important role of cytokines and chemokines in the immunopathogenesis of TBE.
TextSentencer_T238 36137-36230 Sentence denotes This suggests an important role of cytokines and chemokines in the immunopathogenesis of TBE.
TextSentencer_T239 36231-36379 Sentence denotes The host immune response based on the genetic background of the host may therefore play a central role in determining the outcome of TBEV infection.
TextSentencer_T239 36231-36379 Sentence denotes The host immune response based on the genetic background of the host may therefore play a central role in determining the outcome of TBEV infection.
TextSentencer_T240 36380-36398 Sentence denotes Additional file 1:
TextSentencer_T240 36380-36398 Sentence denotes Additional file 1:
TextSentencer_T241 36399-36410 Sentence denotes Figure S1 .
TextSentencer_T241 36399-36410 Sentence denotes Figure S1 .
TextSentencer_T242 36411-36511 Sentence denotes Differential survival of BALB/c, STS and selected RC strains after subcutaneous inoculation of TBEV.
TextSentencer_T242 36411-36511 Sentence denotes Differential survival of BALB/c, STS and selected RC strains after subcutaneous inoculation of TBEV.
TextSentencer_T243 36512-36581 Sentence denotes Mice were inoculated with 104 pfu of TBEV and observed for lethality.
TextSentencer_T243 36512-36581 Sentence denotes Mice were inoculated with 104 pfu of TBEV and observed for lethality.
TextSentencer_T244 36582-36593 Sentence denotes Figure S2 :
TextSentencer_T244 36582-36593 Sentence denotes Figure S2 :
TextSentencer_T245 36594-36695 Sentence denotes Differential survival of BALB/c, STS and selected RC strains after intracerebral inoculation of TBEV.
TextSentencer_T245 36594-36695 Sentence denotes Differential survival of BALB/c, STS and selected RC strains after intracerebral inoculation of TBEV.
TextSentencer_T246 36696-36764 Sentence denotes Mice were inoculated with 10 pfu of TBEV and observed for lethality.
TextSentencer_T246 36696-36764 Sentence denotes Mice were inoculated with 10 pfu of TBEV and observed for lethality.