Virulence of tick-borne encephalitis virus is associated with intact conformational viral RNA structures in the variable region of the 3′-UTR

Sakai, Mayuko; Muto, Memi; Hirano, Michiyo; Kariwa, Hiroaki; Yoshii, Kentaro

doi:10.1016/j.virusres.2015.03.006

Cited by 37 publications

(42 citation statements)

References 33 publications

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“…In line with Sakai et al ., the virus with the longer poly(A) tract was more pathogenic in mice, indicating a putative pathophysiological role of the longer poly(A) tracts that have been detected in Eu-TBEV variants. However, contrary to the previous studies that demonstrated inviolate TBEV replication after poly(A) insertion1119, poly(A) insertion in the V 3′NCR of Torö-2003 restricted viral replication in cell culture. The observed replication discrepancies could be due to the different TBEV subtypes or to higher stability of the replicon RNA used in the respective studies1119.…”

Section: Discussioncontrasting

confidence: 98%

“…Variations in the 3′NCR of tick-borne flaviviruses can be determinants of virulence1112. In previous work we demonstrated the existence of variable 3′NCRs in nature from TBEV strains amplified directly from ticks8.…”

Section: Discussionmentioning

confidence: 84%

“…It was recently established that the V 3′NCR and the poly(A) tract modulate the virulence of FE-TBEV1112. In contrast, previous work has suggested that the V 3′NCR is dispensable for virulence of Eu-TBEV because removal of the complete V 3′NCR had no effect on TBEV virulence9.…”

Section: Discussionmentioning

confidence: 99%

“…The V 3′NCR of Neudoerfl is dispensable for virus replication in cell culture and for virulence in mice9, but in ticks the V 3′NCR was predicted to play an important role in the viral life cycle510. Recent studies with FE-TBEV have shown that the V 3′NCR and poly(A) insertion are important virulence determinants1112, but the underlying pathophysiological mechanism behind this is unclear.…”

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confidence: 99%

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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: Discussioncontrasting

confidence: 98%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Recently, several reports have suggested that UTRs in other viruses are involved in virulence. For example, it has been reported that the variable region of the 3’ UTR of the tick-borne encephalitis virus genome was associated with virulence in mice (31, 32). It has also been reported that UTRs of the picornavirus genome can affect viral infection and host innate immunity (33).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the untranslated region of lymphocytic choriomeningitis virus S segment

Taniguchi

Yoshikawa

Shimojima

et al. 2019

Preprint

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word count: 247 words 21 Importance word count: 116 words. 22 Text word count: 6479 words 23 2 ABSTRACT 24Lymphocytic choriomeningitis virus (LCMV) is a prototypic arenavirus. The viral genome 25 consists of two RNA segments, L and S. The 5'-and 3'-termini of both L and S segments are 26 highly conserved among arenaviruses. These regions consist of 19 complementary base pairs and 27 are essential for viral genome replication and transcription. In addition to these 19 nucleotides in 28 the 5'-and 3'-termini, there are untranslated regions (UTRs) composed of 58 and 41 nucleotide 29 residues in the 5' and 3' UTRs, respectively, in the LCMV S segment. Their functional roles, 30 however, have yet to be elucidated. In this study, a reverse genetics and a minigenome system for 31 the LCMV strain WE were established and used to analyze the function of these regions. The 32 results obtained from these analyses, plus RNA secondary structure prediction, revealed that not 33 only these 19 nucleotides but also the 20th-40th and 20th-38th nucleotides located downstream 34 of the 19 nucleotides in the 5'-and 3'-termini, respectively, are heavily involved in viral genome 35 replication and transcription. Furthermore, the introduction of mutations in these regions 36 depressed viral propagation in vitro and enhanced attenuation in vivo. Conversely, recombinant 37 LCMVs (rLCMVs), which had various deletions in the other UTRs, propagated as well as wild-38 type LCMV in vitro but were attenuated in vivo. Most mice previously infected with rLCMVs 39 with mutated UTRs, when further infected with a lethal dose of wild-type LCMV, survived. 40These results suggest that rLCMVs with mutated UTRs could be candidates for an LCMV 41 vaccine. 42 (247 words) 43 IMPORTANCE 44The function of untranslated regions (UTRs) of the arenavirus genome has not well been studied 45 except for the 19 nucleotides of the 5'-and 3'-termini. In this study the function of the UTRs of 46 the LCMV S segment was analyzed. It was found that not only the 19 nucleotides of the 5'-and 47 3'-termini but also the 20th-40th and 20th-38th nucleotides located downstream of the 19 48 nucleotides in the 5'-and 3'-termini, respectively, were involved in viral genome replication and 49 transcription. Furthermore, other UTRs in the S segment were involved in virulence in vivo. The 50 introduction of mutations to these regions makes it possible to establish attenuated LCMV and 51develop LCMV vaccine candidates. 52 (116 words) 53 54 Lymphocytic choriomeningitis virus (LCMV) belongs to the genus Mammarenavirus, 56 family Arenaviridae. There are two groups of Mammarenavirus, New World and Old World 57 arenaviruses (1). LCMV belongs to the Old World arenavirus group, as does Lassa virus 58 (LASV), the causative agent of Lassa fever. LCMV can infect humans, causing flu-like fever, 59nausea, neck stiffness, headache, and occasionally photophobia. Severe cases can lead to 60 meningitis and encephalitis (2-6). The natural reservoir of LCMV is reported to be the house 61 mouse (Mus muscul...

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Tick‐borne encephalitis: A comprehensive review of the epidemiology, virology, and clinical picture

Chiffi

Grandgirard

Leib

et al. 2023

Reviews in Medical Virology

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Tick‐borne encephalitis virus (TBEV) is a flavivirus commonly found in at least 27 European and Asian countries. It is an emerging public health problem, with steadily increasing case numbers over recent decades. Tick‐borne encephalitis virus affects between 10,000 and 15,000 patients annually. Infection occurs through the bite of an infected tick and, much less commonly, through infected milk consumption or aerosols. The TBEV genome comprises a positive‐sense single‐stranded RNA molecule of ∼11 kilobases. The open reading frame is > 10,000 bases long, flanked by untranslated regions (UTR), and encodes a polyprotein that is co‐ and post‐transcriptionally processed into three structural and seven non‐structural proteins. Tick‐borne encephalitis virus infection results in encephalitis, often with a characteristic biphasic disease course. After a short incubation time, the viraemic phase is characterised by non‐specific influenza‐like symptoms. After an asymptomatic period of 2–7 days, more than half of patients show progression to a neurological phase, usually characterised by central and, rarely, peripheral nervous system symptoms. Mortality is low—around 1% of confirmed cases, depending on the viral subtype. After acute tick‐borne encephalitis (TBE), a minority of patients experience long‐term neurological deficits. Additionally, 40%–50% of patients develop a post‐encephalitic syndrome, which significantly impairs daily activities and quality of life. Although TBEV has been described for several decades, no specific treatment exists. Much remains unknown regarding the objective assessment of long‐lasting sequelae. Additional research is needed to better understand, prevent, and treat TBE. In this review, we aim to provide a comprehensive overview of the epidemiology, virology, and clinical picture of TBE.

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Virulence of tick-borne encephalitis virus is associated with intact conformational viral RNA structures in the variable region of the 3′-UTR

Cited by 37 publications

References 33 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

Characterization of the untranslated region of lymphocytic choriomeningitis virus S segment

Tick‐borne encephalitis: A comprehensive review of the epidemiology, virology, and clinical picture

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