Pathologic Potential of Variant Clones of the Oshima Strain of Far-Eastern Subtype Tick-Borne Encephalitis Virus

Luat, Le Xuan; Tun, Mya Myat Ngwe; Buerano, Corazon C.; Aoki, Kotaro; Morita, Kouichi; Hayasaka, Daisuke

doi:10.2149/tmh.2013-27

Cited by 8 publications

(3 citation statements)

References 40 publications

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“…TBEV is known to exist as clusters of quasispecies within ticks and mammals783839. Quasispecies populations are influenced by the host environment, and changes in the population might affect the phenotype of specific strains40.…”

Section: Discussionmentioning

confidence: 99%

The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus

Asghar

Lee

Nilsson

et al. 2016

Sci Rep

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The tick-borne encephalitis virus (TBEV) is a flavivirus transmitted to humans, usually via tick bites. The virus causes tick-borne encephalitis (TBE) in humans, and symptoms range from mild flu-like symptoms to severe and long-lasting sequelae, including permanent brain damage. It has been suggested that within the population of viruses transmitted to the mammalian host, quasispecies with neurotropic properties might become dominant in the host resulting in neurological symptoms. We previously demonstrated the existence of TBEV variants with variable poly(A) tracts within a single blood-fed tick. To characterize the role of the poly(A) tract in TBEV replication and virulence, we generated infectious clones of Torö-2003 with the wild-type (A)3C(A)6 sequence (Torö-6A) or with a modified (A)3C(A)38 sequence (Torö-38A). Torö-38A replicated poorly compared to Torö-6A in cell culture, but Torö-38A was more virulent than Torö-6A in a mouse model of TBE. Next-generation sequencing of TBEV genomes after passaging in cell culture and/or mouse brain revealed mutations in specific genomic regions and the presence of quasispecies that might contribute to the observed differences in virulence. These data suggest a role for quasispecies development within the poly(A) tract as a virulence determinant for TBEV in mice.

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Section: Discussionmentioning

confidence: 99%

The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus

Asghar

Lee

Nilsson

et al. 2016

Sci Rep

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“…In animal models, other factors contributing to disease severity have been shown besides the host-dependent risk factors, such as the virulence of the particular strain, which could be inconsistent with the TBEV subtype [32] , the inoculation dose [33] , and the immunomodulatory compounds of tick saliva inoculated with virus into the skin [4] . Animal models are also commonly used to elucidate the mechanism of disease development following TBEV infection in vivo and suggest that CNS pathology during TBE is primarily driven by immune response and inflammatory reactions.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in Chemokine Receptor 5 and Toll-Like Receptor 3 Genes Are Risk Factors for Clinical Tick-Borne Encephalitis in the Lithuanian Population

et al. 2014

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BackgroundTick-borne encephalitis virus (TBEV) infections can be asymptomatic or cause moderate to severe injuries of the nervous system. We previously reported that a nonfunctional chemokine receptor 5 (CCR5) and a functional Toll-like receptor 3 (TLR3) predispose adults to clinical tick-borne encephalitis (TBE). This study expands our previous findings and further examines polymorphisms in CCR5 and TLR3 genes in different age and disease severity groups.Methods117 children and 129 adults, stratified into mild, moderate and severe forms of TBE, and 103 adults with severe TBE were analyzed. 135 healthy individuals and 79 patients with aseptic meningoencephalitis served as controls. CCR5 delta 32 and rs3775291 TLR3 genotypes were established by pyrosequencing, and their frequencies were analyzed using recessive genetic, genotype and allelic models.FindingsThe prevalence of CCR5Δ32 homozygotes was higher in children (2.5%), in adults with severe TBE (1.9%), and in the combined cohort of TBE patients (2.3%) than in controls (0%) (p<0.05). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p = 0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. However, in the severe adult TBE cohort, homozygous functional TLR3 genotype and wt allele were less prevalent compared to the adult cohort with the whole disease severity spectrum (44.4% vs 59.8% p = 0.022 and 65.2% vs 76.4% p = 0.009; respectively).ConclusionsIndependently of age, nonfunctional CCR5Δ32 mutation is a significant risk factor for development of clinical TBE, but not for disease severity. The polymorphism of TLR3 gene predisposes to clinical TBE in adults only and may be associated with disease severity. Further studies are needed to clarify the role of these polymorphisms in susceptibility to TBEV infection.

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“…Pathologic potential of variant clones of the Oshima strain of Far-Eastern subtype of TBEV was analyzed in a separate study. It was shown that an amino acid substitution of Glu122 → Gly in the E protein could have affected virus infection and replication in vivo, as well as the attenuated pathogenicity in mice [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

A database of human genes and a gene network involved in response to tick-borne encephalitis virus infection

2017

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BackgroundTick-borne encephalitis is caused by the neurotropic, positive-sense RNA virus, tick-borne encephalitis virus (TBEV). TBEV infection can lead to a variety of clinical manifestations ranging from slight fever to severe neurological illness. Very little is known about genetic factors predisposing to severe forms of disease caused by TBEV. The aims of the study were to compile a catalog of human genes involved in response to TBEV infection and to rank genes from the catalog based on the number of neighbors in the network of pairwise interactions involving these genes and TBEV RNA or proteins.ResultsBased on manual review and curation of scientific publications a catalog comprising 140 human genes involved in response to TBEV infection was developed. To provide access to data on all genes, the TBEVhostDB web resource (http://icg.nsc.ru/TBEVHostDB/) was created. We reconstructed a network formed by pairwise interactions between TBEV virion itself, viral RNA and viral proteins and 140 genes/proteins from TBEVHostDB. Genes were ranked according to the number of interactions in the network. Two genes/proteins (CCR5 and IFNAR1) that had maximal number of interactions were revealed. It was found that the subnetworks formed by CCR5 and IFNAR1 and their neighbors were a fragments of two key pathways functioning during the course of tick-borne encephalitis: (1) the attenuation of interferon-I signaling pathway by the TBEV NS5 protein that targeted peptidase D; (2) proinflammation and tissue damage pathway triggered by chemokine receptor CCR5 interacting with CD4, CCL3, CCL4, CCL2. Among nine genes associated with severe forms of TBEV infection, three genes/proteins (CCR5, IL10, ARID1B) were found to have protein-protein interactions within the network, and two genes/proteins (IFNL3 and the IL10, that was just mentioned) were up- or down-regulated in response to TBEV infection. Based on this finding, potential mechanisms for participation of CCR5, IL10, ARID1B, and IFNL3 in the host response to TBEV infection were suggested.ConclusionsA database comprising 140 human genes involved in response to TBEV infection was compiled and the TBEVHostDB web resource, providing access to all genes was created. This is the first effort of integrating and unifying data on genetic factors that may predispose to severe forms of diseases caused by TBEV. The TBEVHostDB could potentially be used for assessment of risk factors for severe forms of tick-borne encephalitis and for the design of personalized pharmacological strategies for the treatment of TBEV infection.Electronic supplementary materialThe online version of this article (10.1186/s12862-017-1107-8) contains supplementary material, which is available to authorized users.

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Pathologic Potential of Variant Clones of the Oshima Strain of Far-Eastern Subtype Tick-Borne Encephalitis Virus

Cited by 8 publications

References 40 publications

The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus

The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus

Polymorphisms in Chemokine Receptor 5 and Toll-Like Receptor 3 Genes Are Risk Factors for Clinical Tick-Borne Encephalitis in the Lithuanian Population

A database of human genes and a gene network involved in response to tick-borne encephalitis virus infection

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