scholarly journals Glucagon-like peptide-2 receptor is a receptor for tick-borne encephalitis virus to infect nerve cells

2021 ◽  
Author(s):  
Xinwen Chen ◽  
Qi Yang ◽  
Jizheng Chen ◽  
Rongjuan Pei ◽  
Yun Wang ◽  
...  
Keyword(s):  
Nerve Cells ◽  
Encephalitis Virus ◽  
Viral Envelope ◽  
Infectious Dose ◽  
Tick Borne Encephalitis ◽  
A Genome ◽  
Glucagon Like Peptide ◽  
Tick Borne Encephalitis Virus ◽  
Tbev Infection ◽  
Deficient Mice

Abstract Tick-borne encephalitis virus (TBEV) is a tick-borne flavivirus that causes severe encephalitis disease1,2. Host proteins required for TBEV entry remain largely unknown3. Here we performed a genome-wide CRISPR-Cas9 knockout screen and identified G-protein-coupled receptor glucagon-like peptide-2 receptor (GLP2R) as a receptor for TBEV to infect nerve cells. Knockdown or knockout of GLP2R reduced TBEV infection of different nerve cells; trans supply of GLP2R restored viral infection. GLP2R directly binds to viral envelope domain III through its extracellular loop 1 (ECL1). TBEV infection can be blocked by the ECL1 peptide, a functional ligand to GLP2R, or GLP2R antibodies. GLP2R-deficient mice were generated to validate the role of GLP2R in TBEV infection and pathogenesis. Wild-type mice succumbed to TBEV infection and developed >107 TCID50 (median tissue culture infectious dose) virus per gram of brain tissue. In contrast, all GLP2R-deficient mice survived TBEV infection without detectable infectious virus in brain. Altogether, our results support GLP2R as a receptor for TBEV to infect nerve cells.

scholarly journals Infection and injury of human astrocytes by tick-borne encephalitis virus

2014 ◽  
Vol 95 (11) ◽  
pp. 2411-2426 ◽  
Author(s):  
Martin Palus ◽  
Tomáš Bílý ◽  
Jana Elsterová ◽  
Helena Langhansová ◽  
Jiří Salát ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Encephalitis Virus ◽  
Ultrastructural Changes ◽  
Interferon Α ◽  
Human Astrocytes ◽  
Tick Borne Encephalitis ◽  
Infected Cells ◽  
Tick Borne Encephalitis Virus ◽  
Tbev Infection ◽  
Pro Inflammatory Cytokines

Tick-borne encephalitis (TBE), a disease caused by tick-borne encephalitis virus (TBEV), represents the most important flaviviral neural infection in Europe and north-eastern Asia. In the central nervous system (CNS), neurons are the primary target for TBEV infection; however, infection of non-neuronal CNS cells, such as astrocytes, is not well understood. In this study, we investigated the interaction between TBEV and primary human astrocytes. We report for the first time, to the best of our knowledge, that primary human astrocytes are sensitive to TBEV infection, although the infection did not affect their viability. The infection induced a marked increase in the expression of glial fibrillary acidic protein, a marker of astrocyte activation. In addition, expression of matrix metalloproteinase 9 and several key pro-inflammatory cytokines/chemokines (e.g. tumour necrosis factor α, interferon α, interleukin (IL)-1β, IL-6, IL-8, interferon γ-induced protein 10, macrophage inflammatory protein, but not monocyte chemotactic protein 1) was upregulated. Moreover, we present a detailed description of morphological changes in TBEV-infected cells, as investigated using three-dimensional electron tomography. Several novel ultrastructural changes were observed, including the formation of unique tubule-like structures of 17.9 ±0.15 nm diameter with associated viral particles and/or virus-induced vesicles and located in the rough endoplasmic reticulum of the TBEV-infected cells. This is the first demonstration that TBEV infection activates primary human astrocytes. The infected astrocytes might be a potential source of pro-inflammatory cytokines in the TBEV-infected brain, and might contribute to the TBEV-induced neurotoxicity and blood–brain barrier breakdown that occurs during TBE. The neuropathological significance of our observations is also discussed.

scholarly journals A Functional Toll-Like Receptor 3 Gene (TLR3) May Be a Risk Factor for Tick-borne Encephalitis Virus (TBEV) Infection

2011 ◽  
Vol 203 (4) ◽  
pp. 523-528 ◽  
Author(s):  
Elin Kindberg ◽  
Sirkka Vene ◽  
Aukse Mickiene ◽  
Åke Lundkvist ◽  
Lars Lindquist ◽  
...  
Keyword(s):  
Risk Factor ◽  
Encephalitis Virus ◽  
Toll Like Receptor ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus ◽  
Tbev Infection

scholarly journals Nucleoside Inhibitors of Tick-Borne Encephalitis Virus

2015 ◽  
Vol 59 (9) ◽  
pp. 5483-5493 ◽  
Author(s):  
Luděk Eyer ◽  
James J. Valdés ◽  
Victor A. Gil ◽  
Radim Nencka ◽  
Hubert Hřebabecký ◽  
...  
Keyword(s):  
Neuroblastoma Cells ◽  
Antiviral Effect ◽  
Encephalitis Virus ◽  
Nucleoside Analogues ◽  
Kidney Cells ◽  
Porcine Kidney ◽  
Human Neuroblastoma ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus ◽  
Tbev Infection

ABSTRACTTick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza-2′-C-methyladenosine (7-deaza-2′-CMA), 2′-C-methyladenosine (2′-CMA), and 2′-C-methylcytidine (2′-CMC) inhibited TBEV replication. These compounds showed dose-dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC50]of 5.1 ± 0.4 μM for 7-deaza-2′-CMA, 7.1 ± 1.2 μM for 2′-CMA, and 14.2 ± 1.9 μM for 2′-CMC) and viral antigen production. Notably, 2′-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of ∼50 μM). The anti-TBEV effect of 2′-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2′-CMA showed no detectable cellular toxicity (CC50> 50 μM), and the antiviral effect in culture was stable for >6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2′-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2′-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection.

TBE in France

2019 ◽  
Author(s):  
Yves Hansmann ◽  
Aurélie Velay
Keyword(s):  
Human Case ◽  
Encephalitis Virus ◽  
Eastern Region ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus ◽  
Tbev Infection

The first human case of tick-borne encephalitis virus (TBEV) infection in France was reported in 1968 in Alsace, an eastern region next to the German border: a gamekeeper working in a forest near Strasbourg.

scholarly journals First human case of tick-borne encephalitis virus infection acquired in the Netherlands, July 2016

2016 ◽  
Vol 21 (33) ◽  
Author(s):  
Joris A de Graaf ◽  
Johan H J Reimerink ◽  
G Paul Voorn ◽  
Elisabeth A bij de Vaate ◽  
Ankje de Vries ◽  
...  
Keyword(s):  
Virus Infection ◽  
The Netherlands ◽  
Human Case ◽  
Encephalitis Virus ◽  
Tick Bite ◽  
Travel History ◽  
Qrt Pcr ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus ◽  
Tbev Infection

In July 2016, the first autochthonous case of tick-borne encephalitis was diagnosed in the Netherlands, five days after a report that tick-borne encephalitis virus (TBEV) had been found in Dutch ticks. A person in their 60s without recent travel history suffered from neurological symptoms after a tick bite. TBEV serology was positive and the tick was positive in TBEV qRT-PCR. TBEV infection should be considered in patients with compatible symptoms in the Netherlands.

The role of IFITM proteins in tick-borne encephalitis virus infection

2021 ◽  
Author(s):  
Alicja M. Chmielewska ◽  
Maria Gómez-Herranz ◽  
Paulina Gach ◽  
Marta Nekulova ◽  
Małgorzata Tyrakowska ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Encephalitis Virus ◽  
Restriction Factors ◽  
Northern Asia ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus ◽  
Tbev Infection ◽  
Cell Spread

Tick-borne encephalitis virus (TBEV), of the genus Flavivirus, is a causative agent of severe encephalitis in endemic regions of northern Asia and central and northern Europe. Interferon induced transmembrane proteins (IFITMs) are restriction factors that inhibit the replication cycles of numerous viruses, including flaviviruses such as the West Nile virus, dengue virus, and Zika virus. Here, we demonstrate the role of IFITM1, IFITM2, and IFITM3 in the inhibition of TBEV infection and in protection against virus-induced cell death. We show the most significant role being that of IFITM3, including the dissection of its functional motifs by mutagenesis. Furthermore, through the use of CRISPR–Cas9-generated IFITM1/3-knockout monoclonal cell lines, we confirm the role and additive action of endogenous IFITMs in TBEV suppression. However, the results of co-culture assays suggest that TBEV might partially escape IFN- and IFITM-mediated suppression during high-density co-culture infection when the virus enters naïve cells directly from infected donor cells. Thus, cell-to-cell spread may constitute a strategy for virus escape from innate host defenses. Importance: TBEV infection may result in encephalitis, chronic illness or death. TBEV is endemic in northern Asia and Europe; however, due to climate change, new endemic centers arise. Although effective TBEV vaccines have been approved, vaccination coverage is low, and, due to the lack of specific therapeutics, infected individuals depend on their immune responses to control the infection. The IFITM proteins are components of the innate antiviral defenses that suppress cell entry of many viral pathogens. However, no studies regarding the role of IFITM proteins in the TBEV infection have been published so far. Understanding of antiviral innate immune responses is crucial for future development of antiviral strategies. Here, we show the important role of IFITM proteins in the inhibition of TBEV infection and virus-mediated cell death. However, our data suggest that TBEV cell-to-cell spread may be less prone to both IFN- and IFITM-mediated suppression, potentially facilitating escape from IFITM-mediated immunity.

scholarly journals Sequential MAVS- and MyD88/TRIF-signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes

2020 ◽  
Author(s):  
Luca Ghita ◽  
Veronika Breitkopf ◽  
Felix Mulenge ◽  
Andreas Pavlou ◽  
Olivia Luise Gern ◽  
...  
Keyword(s):  
Cell Subset ◽  
Encephalitis Virus ◽  
Type I ◽  
Tick Borne Encephalitis ◽  
Transcriptome Analyses ◽  
Tick Borne Encephalitis Virus ◽  
Viral Responses ◽  
Mitochondrial Antiviral Signaling ◽  
Tbev Infection

AbstractTick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is typically transmitted upon tick bite and can cause meningitis and encephalitis in humans. In TBEV infected mice, mitochondrial antiviral signaling protein (MAVS), the downstream adaptor of retinoic acid inducible gene I-like receptor (RLR)-signaling, is needed to induce early type I interferon (IFN) responses and to confer protection. To identify the brain resident cell subset that produces protective IFN-β in TBEV infected mice, we isolated neurons, astrocytes and microglia and exposed these cells to TBEV in vitro. Under such conditions, neurons showed the highest percentage of infected cells, whereas astrocytes and microglia were infected to a lesser extent. In the supernatant (SN) of infected neurons, IFN-β was not detectable, while infected astrocytes showed very high and microglia low IFN-β production. Transcriptome analyses of astrocytes implied that MAVS-signaling was needed early after TBEV infection. Accordingly, MAVS-deficient astrocytes showed enhanced TBEV infection and significantly reduced early IFN-β responses. At later time points, moderate amounts of IFN-β were detected in the SN of infected MAVS-deficient astrocytes. Transcriptome analyses indicated that MAVS-deficiency negatively affected the induction of early anti-viral responses, which resulted in significantly increased TBEV replication. Treatment with MyD88 and TRIF inhibiting peptides reduced late IFN-β responses of TBEV infected WT astrocytes and entirely blocked IFN-β responses of infected MAVS-deficient astrocytes. Thus, upon TBEV exposure of brain-resident cells, astrocytes are important IFN-β producers that show biphasic IFN-β induction that initially depends on MAVS- and later on MyD88/TRIF-signaling.

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