Tick-borne encephalitis virus inhibits rRNA synthesis and host protein production in human cells of neural origin

Selinger, Martin; Tykalová, Hana; Štěrba, Ján; Vechtova, Pavlina; Vavrušková, Zuzana; Lieskovská, Jaroslava; Kohl, Alain; Schnettler, Esther; Grubhoffer, Libor

doi:10.1371/journal.pntd.0007745

Cited by 14 publications

(8 citation statements)

References 63 publications

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“…We next aimed to compare the phenotypic characteristics of the rescued TBEV-Eu strain Salland to two well-characterized TBEV-Eu strains of known pathogenicity. For this, the TBEV-Eu reference strain Neudoerfl, which was isolated from ticks in 1971 and shows low to medium pathogenic potential 33 , was acquired through the European Virus Archive, whereas Hypr, a TBEV-Eu strain originally isolated from the blood of a deceased child in 1953 and which is considered highly virulent 29 , 33 – 35 , was acquired using Infectious Subgenomic Amplicons.…”

Section: Resultsmentioning

confidence: 99%

“…Evidently, caution needs to be taken when extrapolating in vitro data to the situation in vivo. Yet, multiple studies have previously shown that TBEV replication efficiency in vitro is often associated with pathogenicity in vivo 29 , 30 , 33 , 35 , 47 , 48 , with highly pathogenic strains replicating faster and to higher titers than mildly pathogenic strains in a multitude of cell lines 29 , 30 , 35 , 47 , 48 and human whole blood samples infected ex vivo 49 . Nonetheless, reports in which TBEV growth kinetics in vitro do not directly correlate with pathogenicity in vivo are also known.…”

Section: Discussionmentioning

confidence: 99%

“…In the CNS, neurons seem to be the main target cells of TBEV 7 , 64 , 65 . Being often used in TBEV pathogenicity studies 29 , 35 , 47 , 66 , 67 , the cell types used in this study served as suitable and convenient models for initial characterization of the TBEV-Eu strain Salland. To confirm the findings obtained in this study, further studies using more differentiated cell cultures in vitro, including neurons and Langerhans cells, and in vivo infection experiments need to be performed.…”

Section: Discussionmentioning

confidence: 99%

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Rescue and in vitro characterization of a divergent TBEV-Eu strain from the Netherlands

Hoornweg

Godeke

Hoogerwerf

et al. 2023

Sci Rep

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Tick-borne encephalitis virus (TBEV) may cause tick-borne encephalitis (TBE), a potential life-threatening infection of the central nervous system in humans. Phylogenetically, TBEVs can be subdivided into three main subtypes, which differ in endemic region and pathogenic potential. In 2016, TBEV was first detected in the Netherlands. One of two detected strains, referred to as Salland, belonged to the TBEV-Eu subtype, yet diverged ≥ 2% on amino acid level from other members of this subtype. Here, we report the successful rescue of this strain using infectious subgenomic amplicons and its subsequent in vitro characterization by comparison to two well-characterized TBEV-Eu strains; Neudoerfl and Hypr. In the human alveolar epithelial cell line A549, growth kinetics of Salland were comparable to the high pathogenicity TBEV-Eu strain Hypr, and both strains grew considerably faster than the mildly pathogenic strain Neudoerfl. In the human neuroblastoma cell line SK-N-SH, Salland replicated faster and to higher infectious titers than both reference strains. All three TBEV strains infected primary human monocyte-derived dendritic cells to a similar extent and interacted with the type I interferon system in a similar manner. The current study serves as the first in vitro characterization of the novel, divergent TBEV-Eu strain Salland.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Rescue and in vitro characterization of a divergent TBEV-Eu strain from the Netherlands

Hoornweg

Godeke

Hoogerwerf

et al. 2023

Sci Rep

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“…The observed accelerated degradation of ubiquitinated proteins was probably due to the suppression of de novo protein synthesis ( Figure 7 (e)). Recently, it has been reported that suppression of host de novo protein synthesis is a hallmark of flavivirus infection [ 46 , 52 , 53 ]. We propose that it might be a common strategy for flaviviruses to suppress host de novo protein synthesis to accelerate proteasomal degradation of short-lived antiviral proteins to antagonize IFN signalling, as YFV similarly suppressed host de novo protein synthesis (Supplementary Figure 9).…”

Section: Resultsmentioning

confidence: 99%

NS5-independent Ablation of STAT2 by Zika virus to antagonize interferon signalling

Shu

Yang

et al. 2021

Emerging Microbes & Infections

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Flavivirus genus includes numerous arthropod-borne human pathogens that are clinically important. Flaviviruses are notorious for their ability to antagonize host interferon (IFN) induced anti-viral signalling. It has been documented that NS5s of flaviviruses mediate proteasome degradation of STAT2 to evade IFN signalling. Deciphering the molecular mechanism of the IFN antagonism by the viruses and reversing this antagonism may dictate anti-viral responses and provide novel antiviral approaches. In this report, by using Zika virus (ZIKV) as a model, we first demonstrated that ZIKV antagonized interferon signalling in an infectious dose-dependent manner; in other words, the virus antagonized interferon signalling at a high multiple of infection (MOI) and was sensitive to interferon signalling at a low MOI. Mechanistically, we found that ZIKV infection triggered degradation of ubiquitinated STAT2 and host short-lived proteins while didn't affect the proteasome activity per se . ZIKV infection resulted in suppression of host de novo protein synthesis. Overexpression of NS5 alone only marginally reduced STAT2 and had no effect on the host de novo protein synthesis. Ectopically expressed murine STAT2 that was resistant to NS5- and ZIKV-induced ablation exaggerated the IFN-induced anti-viral signalling. These data favour a new model of the innate immune evasion of ZIKV in which the viral infection triggers suppression of host de novo protein synthesis to accelerate the degradation of short-lived, ubiquitinated STAT2. As flaviviruses share a very conserved replication strategy, the mechanisms of IFN antagonism elucidated here might also be employed by other flaviviruses.

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“…Quantification was determined based on the ratio of total fluorescent intensity of IL‐1β relative to the nuclei (DAPI stain). Analyses were performed using ImageJ software (NIH, USA) (Selinger et al., 2019) to determine the pro‐ and mature IL‐1β levels.…”

Section: Methodsmentioning

confidence: 99%

Inflammasome dysregulation in human gingival fibroblasts in response to periodontal pathogens

2021

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Objective Uncontrolled production of Interleukin‐1β (IL‐1β), a major proinflammatory cytokine, is associated with tissue destruction in periodontal disease. IL‐1β production is controlled by inflammasomes which are multiprotein regulatory complexes. The current study aimed to elucidate potential regulatory pathways by monitoring the effects of periodontal pathogens Fusobacterium nucleatum (Fn) and Porphyromonas gingivalis (Pg) on inflammasomes and their regulators in human gingival fibroblasts (HGFs) in vitro. Methods HGFs were exposed to Fn and Pg alone or in combination for 24 hr at a multiplicity of infection of 100, ±30 min exposure with 5 mM adenosine triphosphate (ATP) incubation. Gene expression of NLRP3 and AIM2, inflammasome regulatory proteins POP1, CARD16 and TRIM16, and inflammasome components ASC and CASPASE 1, and IL‐1β, were evaluated by RT‐PCR. Pro‐ and mature IL‐1β levels were monitored intracellularly by immunocytochemistry and extracellularly by ELISA. Results Fn + ATP significantly upregulated NLRP3, AIM2, IL‐1β, ASC, and CASPASE 1; however, it downregulated POP1 and TRIM16. Pg + ATP downregulated NLRP3, ASC, POP1, but upregulated IL‐1β and CARD16. Pg + Fn+ATP significantly upregulated AIM2, IL‐1β and CARD16, and downregulated POP1, TRIM16, and CASPASE 1. Pg + ATP exposure significantly increased pro‐ and mature IL‐1β production. Conclusion Bacterial exposure with ATP may deregulate IL‐1β by dysregulating inflammasomes and their regulators in HGFs.

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Tick-borne encephalitis virus inhibits rRNA synthesis and host protein production in human cells of neural origin

Cited by 14 publications

References 63 publications

Rescue and in vitro characterization of a divergent TBEV-Eu strain from the Netherlands

Rescue and in vitro characterization of a divergent TBEV-Eu strain from the Netherlands

NS5-independent Ablation of STAT2 by Zika virus to antagonize interferon signalling

Inflammasome dysregulation in human gingival fibroblasts in response to periodontal pathogens

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