Tick-Borne Encephalitis Virus Infects Rat Astrocytes but Does Not Affect Their Viability

Potokar, Maja; Korva, Miša; Jorgačevski, Jernej; Avšič-Županc, Tatjana; Zorec, Robert

doi:10.1371/journal.pone.0086219

Cited by 57 publications

(111 citation statements)

References 64 publications

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“…Previous studies have revealed that although TBEV infects astrocytes, viral infection did not affect the viability of the cells [34,35]. Similar findings have been observed with other viral infections such as WNV, JEV, and Junin virus whereas infection with Venezuelan equine encephalitis virus infection induced cell death in cultured astrocytes [31,37,39,85,86].…”

Section: Discussionsupporting

confidence: 77%

“…This indicated that response to type I IFN is more important for restricting viral growth than the basal expression level of antiviral ISGs. Previous studies have shown that astrocytes are resistant to TBEV-induced cytopathic effects [34,35]. We can now show that the viability of WT astrocytes after TBEV infection is dependent on the type 1 IFN response, since IFNAR −/− , as well as WT astrocytes treated with an IFNAR-specific antibody, rendered them susceptible to TBEV-induced cytopathic effect 48 hpi (Fig.…”

Section: Ifn Signaling Restricts Tbev Spread In Astrocytessupporting

confidence: 58%

“…They resist infection in an interferon-beta promoter stimulator 1 (IPS-1)-dependent manner and show an activated phenotype, indicating their involvement in LGTV clearance. Both rat and human astrocytes have been shown to be infected in vitro with TBEV; however, the number of infected cells never exceeded 20 %, and the infection did not affect astrocyte viability [34,35]. Similar findings have also been observed for other neurotropic flaviviruses [36][37][38][39].…”

Section: Introductionsupporting

confidence: 60%

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Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects

Lindqvist

Mundt

Gilthorpe

et al. 2016

J Neuroinflammation

125

152

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BackgroundNeurotropic flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne flavivirus infection. However, the cells responsible for mounting this protective response are not defined.MethodsPrimary astrocytes were isolated from wild-type (WT) and interferon alpha receptor knock out (IFNAR−/−) mice and infected with neurotropic flaviviruses. Viral replication and spread, IFN induction and response, and cellular viability were analyzed. Transcriptional levels in primary astrocytes treated with interferon or supernatant from virus-infected cells were analyzed by RNA sequencing and evaluated by different bioinformatics tools.ResultsHere, we show that astrocytes control viral replication of different TBEV strains, JEV, WNV, and ZIKV. In contrast to fibroblast, astrocytes mount a rapid interferon response and restrict viral spread. Furthermore, basal expression levels of key interferon-stimulated genes are high in astrocytes compared to mouse embryonic fibroblasts. Bioinformatic analysis of RNA-sequencing data reveals that astrocytes have established a basal antiviral state which contributes to the rapid viral recognition and upregulation of interferons. The most highly upregulated pathways in neighboring cells were linked to type I interferon response and innate immunity. The restriction in viral growth was dependent on interferon signaling, since loss of the interferon receptor, or its blockade in wild-type cells, resulted in high viral replication and virus-induced cytopathic effects. Astrocyte supernatant from TBEV-infected cells can restrict TBEV growth in astrocytes already 6 h post infection, the effect on neurons is highly reinforced, and astrocyte supernatant from 3 h post infection is already protective.ConclusionsThese findings suggest that the combination of an intrinsic constitutive antiviral response and the fast induction of type I IFN production by astrocytes play an important role in self-protection of astrocytes and suppression of flavivirus replication in the CNS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0748-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 77%

Section: Ifn Signaling Restricts Tbev Spread In Astrocytessupporting

confidence: 58%

Section: Introductionsupporting

confidence: 60%

See 1 more Smart Citation

Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects

Lindqvist

Mundt

Gilthorpe

et al. 2016

J Neuroinflammation

125

152

View full text Add to dashboard Cite

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“…While working with infectious, radiolabeled virus particles may be inconvenient, the use of high MOIs is potentially more problematic, since aggregates of virus particles can influence the apparent mechanisms of viral entry (43). More recently, the entry of individual, fluorescently labeled flavivirus particles has been visualized at low MOIs through live cell imaging (30,(44)(45)(46). An important caveat to this approach is that flavivirus preparations typically have relatively low specific infectivities (44,45,47), so it is difficult to know whether a given particle under observation is on a pathway toward productive infection.…”

Section: Discussionmentioning

confidence: 99%

A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

Ramanathan

Zhang

Douam

et al. 2020

mBio

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While the basic mechanisms of flavivirus entry and fusion are understood, little is known about the postfusion events that precede RNA replication, such as nucleocapsid disassembly. We describe here a sensitive, conditionally replicationdefective yellow fever virus (YFV) entry reporter, YFVΔSK/Nluc, to quantitively monitor the translation of incoming, virus particle-delivered genomes. We validated that YFVΔSK/Nluc gene expression can be neutralized by YFV-specific antisera and requires known flavivirus entry pathways and cellular factors, including clathrin-and dynamin-mediated endocytosis, endosomal acidification, YFV E glycoprotein-mediated fusion, and cellular LY6E and RPLP1 expression. The initial round of YFV translation was shown to require cellular ubiquitylation, consistent with recent findings that dengue virus capsid protein must be ubiquitylated in order for nucleocapsid uncoating to occur. Importantly, translation of incoming YFV genomes also required valosin-containing protein (VCP)/p97, a cellular ATPase that unfolds and extracts ubiquitylated client proteins from large complexes. RNA transfection and washout experiments showed that VCP/p97 functions at a postfusion, pretranslation step in YFV entry. Finally, VCP/p97 activity was required by other flaviviruses in mammalian cells and by YFV in mosquito cells. Together, these data support a critical role for VCP/p97 in the disassembly of incoming flavivirus nucleocapsids during a postfusion step in virus entry. IMPORTANCE Flaviviruses are an important group of RNA viruses that cause significant human disease. The mechanisms by which flavivirus nucleocapsids are disassembled during virus entry remain unclear. Here, we used a yellow fever virus entry reporter, which expresses a sensitive reporter enzyme but does not replicate, to show that nucleocapsid disassembly requires the cellular protein-disaggregating enzyme valosin-containing protein, also known as p97.

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“…Within the CNS, neurons are the primary target for infection by TBEV and undergo apoptosis (59–62). While astrocytes can also become infected, these cells appear to be primarily involved in cytokine production and do not undergo morphological changes or apoptosis (63, 64). We do show that LGTV antigen co-localized to areas of apoptotic cells, and based on previous literature, these infected cells may be primarily neurons and/or neutrophils (35, 59–62).…”

Section: Discussionmentioning

confidence: 99%

Dual Function of Ccr5 during Langat Virus Encephalitis: Reduction in Neutrophil-Mediated Central Nervous System Inflammation and Increase in T Cell–Mediated Viral Clearance

Michlmayr

Bardina

Rodriguez

et al. 2016

The Journal of Immunology

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Tick-borne encephalitis virus (TBEV) is a vector-transmitted flavivirus that causes potentially fatal neurological infection. There are thousands of cases reported annually, and despite the availability of an effective vaccine, the incidence of TBEV is increasing worldwide. Importantly, up to thirty percent of affected individuals will develop long-term neurologic sequelae. We investigated the role of chemokine receptor Ccr5 in a mouse model of TBEV infection using the naturally attenuated tick-borne flavivirus, Langat virus (LGTV). Ccr5-deficient mice presented with an increase in viral replication within the CNS and decreased survival during LGTV encephalitis when compared to wild type (WT) controls. This enhanced susceptibility was due to the temporal lag in lymphocyte migration into the CNS. Adoptive transfer of WT T cells, but not Ccr5-deficient T cells, was able to significantly improve survival outcome in LGTV-infected Ccr5-deficient mice. Concomitantly, a significant increase in neutrophil migration into the CNS in LGTV-infected Ccr5−/− mice was documented at the late stage of infection. Antibody-mediated depletion of neutrophils in Ccr5−/− mice resulted in a significant improvement in mortality, a decrease in viral load, and a decrease in overall tissue damage in the CNS when compared to isotype control-treated mice. Ccr5 is crucial in not only directing T cells towards the LGTV-infected brain, but also in suppressing neutrophil-mediated inflammation within the CNS.

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Tick-Borne Encephalitis Virus Infects Rat Astrocytes but Does Not Affect Their Viability

Cited by 57 publications

References 64 publications

Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects

Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects

A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

Dual Function of Ccr5 during Langat Virus Encephalitis: Reduction in Neutrophil-Mediated Central Nervous System Inflammation and Increase in T Cell–Mediated Viral Clearance

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