Viral Determinants of Virulence in Tick-Borne Flaviviruses

Kellman, Eliza M.; Offerdahl, Danielle K.; Melik, Wessam; Bloom, Marshall E.

doi:10.3390/v10060329

Cited by 40 publications

(56 citation statements)

References 105 publications

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“…Conversely, the two seabird-associated TBFVs with available 3’UTR data, Tyuleniy virus (TYUV) and Kama virus (KAMV) do not fit into this general scheme. Likewise, we were not able to annotate additional homologous or conserved structures with any CM used in this screen in the variable region of the 3’UTR of TBEV [5], despite the substantially longer UTR (+300 nts).…”

Section: Resultsmentioning

confidence: 99%

Functional RNA Structures in the 3’UTR of Tick-Borne, Insect-Specific and No-Known-Vector Flaviviruses

Ochsenreiter

Hofacker

Wolfinger

2019

Preprint

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Untranslated regions (UTRs) of flaviviruses contain a large number of RNA structural 1 elements involved in mediating the viral life cycle, including cyclisation, replication, and 2 encapsidation. Here we report on a comparative genomics approach to characterize evolutionarily 3 conserved RNAs in the 3'UTR of tick-borne, insect-specific and no-known-vector flaviviruses in silico. 4 Our data support the wide distribution of previously experimentally characterized exoribonuclease 5 resistant RNAs (xrRNAs) within tick-borne and no-known-vector flaviviruses and provide evidence 6 for the existence of a cascade of duplicated RNA structures within insect-specific flaviviruses. On a 7 broader scale, our findings indicate that viral 3'UTRs represent a flexible scaffold for evolution to 8 come up with novel xrRNAs.9

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Section: Resultsmentioning

confidence: 99%

Functional RNA Structures in the 3’UTR of Tick-Borne, Insect-Specific and No-Known-Vector Flaviviruses

Ochsenreiter

Hofacker

Wolfinger

2019

Preprint

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“…The E protein is involved in receptor binding and membrane fusion and could be of great importance for fast spread and infection within the brain. Apart from its role in receptor binding and membrane fusion, the E protein also constitutes the most important antigenic structure [38]. Previous studies have indicated that the E protein is important for pathogenesis, amino acid changes in the E protein which resulted in increased net positive charge showed lower pathogenicity and neuroinvasiveness in vivo [22,41,44].…”

Section: Discussionmentioning

confidence: 99%

“…Residue 83 in domain II was found to be located on the surface of the virion particle whereas residue 463 is burried in the membrane. The E protein is involved in receptor binding, membran fusion and also constitute the main target for neutralizing antibodies [38,39], thus the E protein plays an important role in pathogenesis. To determine the function of these amino acid substitutions, a chimeric Torö virus was generated replacing the E protein with the E protein of 93/783, denoted Torö93E (Fig.…”

Section: Rna Isolation and Qpcrmentioning

confidence: 99%

The Envelope Protein of Tick-Borne Encephalitis Virus Influence Neuron Entry, Pathogenicity and Vaccine Protection

Lindqvist

Rosendal

Asghar

et al. 2020

Preprint

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Background: Tick-borne encephalitis virus (TBEV) is considered to be the medically most important arthropod-borne virus in Europe. The symptoms of an infection ranges from subclinical to mild flu-like disease to lethal encephalitis. The exact determinants of disease severity are not known, however, the virulence of the strain as well as the immune status of the host are thought to be important factors for the outcome of the infection. Here we investigated virulence determinants in TBEV infection.Method: Mice were infected with different TBEV strains, and high virulent and low virulent TBEV were chosen. Sequence alignment were used to identify differences that were cloned to generate chimera virus. The infection rate of the parental and chimeric virus were evaluated in primary mouse neurons, astrocytes and MEFs. Neutralizing capacity of serum from individuals vaccinated with the FSME-IMMUN® and Encepur® or combined were evaluated.Results: We identified a highly pathogenic and neurovirulent TBEV strain, 93/783. Using sequence analysis, we identified the envelope (E) protein of 93/783 as a potential virulence determinant and cloned it into the less pathogenic TBEV strain Torö. We found that the chimeric virus specifically infected primary neurons more efficiently compared to wild type (WT) Torö and this correlated with enhanced pathogenicity in vivo. The E protein is also the major target of neutralizing antibodies, thus genetic variation in the E protein could influence the efficiency of the two available vaccines, FSME-IMMUN® and Encepur®. As TBEV vaccine breakthroughs have occurred in Europe, we choose to compare neutralizing capacity from individuals vaccinated with the two different vaccines or a combination of them. Our data suggest that the different vaccines do not perform equally well against the two Swedish strains.Conclusions: Our findings show that two amino acid substitutions of the E protein found in 93/783, A83T and A463S, enhanced Torö infection of neurons as well as pathogenesis in vivo, furthermore we found that genetic divergence from the vaccine strain resulted in lower neutralizing antibody titers in vaccinated individuals.

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“…Tick-borne encephalitis virus (TBEV) is an arthropodborne flavivirus that causes a febrile disease in humans that sometimes progresses to encephalitis, with mortality rates as high as 20-30% (52). The nonstructural protein (NS) 5, the most conserved flaviviral protein, is a methyltransferase and an RNA-dependent RNA polymerase involved in viral genome replication (53,54) and has an important role in immune evasion because of its potent inhibition of type I IFN (55)(56)(57). TBEV NS5 has 2 PDZbms: a canonical CT type I (SSII) and an internal PDZbm (EMYYS) within the methyltransferase domain (58).…”

Section: Tick-borne Encephalitis Virusmentioning

confidence: 99%

Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

Gutiérrez‐González¹,

Santos‐Mendoza

2019

FASEB j.

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PDZ proteins are highly conserved through evolution; the principal function of this large family of proteins is to assemble protein complexes that are involved in many cellular processes, such as cell‐cell junctions, cell polarity, recycling, or trafficking. Many PDZ proteins that have been identified as targets of viral pathogens by promoting viral replication and spread are also involved in epithelial cell polarity. Here, we briefly review the PDZ polarity proteins in cells of the immune system to subsequently focus on our hypothesis that the viral PDZ‐dependent targeting of PDZ polarity proteins in these cells may alter the cellular fitness of the host to favor that of the virus; we further hypothesize that this modification of the cellular fitness landscape occurs as a common and widespread mechanism for immune evasion by viruses and possibly other pathogens.—Gutiérrez‐González, L. H., Santos‐Mendoza, T. Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism. FASEB J. 33, 10607–10617 (2019). http://www.fasebj.org

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Viral Determinants of Virulence in Tick-Borne Flaviviruses

Cited by 40 publications

References 105 publications

Functional RNA Structures in the 3’UTR of Tick-Borne, Insect-Specific and No-Known-Vector Flaviviruses

Functional RNA Structures in the 3’UTR of Tick-Borne, Insect-Specific and No-Known-Vector Flaviviruses

The Envelope Protein of Tick-Borne Encephalitis Virus Influence Neuron Entry, Pathogenicity and Vaccine Protection

Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

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