Cell-type- and region-specific restriction of neurotropic flavivirus infection by viperin

Lindqvist, Richard; Kurhade, Chaitanya; Gilthorpe, Jonathan; Överby, Anna K.

doi:10.1186/s12974-018-1119-3

Cited by 46 publications

(57 citation statements)

References 54 publications

(78 reference statements)

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“…Two other antiviral genes usually more robustly induced by type I than type II IFNs, Rsad2 and Zc3hav1, were induced later and to lesser extents. Rsad2-encoded viperin can impair budding of enveloped viruses [47][48][49] and alphavirus and flavivirus replication and assembly [50][51][52][53]. Zc3hav1 encodes zinc-finger antiviral protein (ZAP) or poly(ADP-ribose) polymerase-13 (PARP13), an RNA-binding protein that recruits RNA decay factors to degrade viral RNA and inhibit viral RNA translation [54][55][56][57][58].…”

Section: Discussionmentioning

confidence: 99%

Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis

Baxter

Griffin

2020

Viruses

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Infection of mice with Sindbis virus (SINV) provides a model for examining the role of the immune response to alphavirus infection of the central nervous system (CNS). Interferon-gamma (IFN-γ) is an important component of this response, and we show that SINV-infected differentiated neurons respond to IFN-γ in vitro by induction of antiviral genes and suppression of virus replication.To determine the in vivo effects of IFN-γ on SINV clearance and T cell responses, C57BL/6 mice lacking IFN-γ or IFN-γ receptor-1 were compared to wild-type (WT) mice after intracranial SINV infection. In WT mice, IFN-γ was first produced in the CNS by natural killer cells and then by CD4 + and CD8 + T cells. Mice with impaired IFN-γ signaling initiated clearance of viral RNA earlier than WT mice associated with CNS entry of more granzyme B-producing CD8 + T cells. However, these mice established fewer CD8 + tissue-resident memory T (T RM ) cells and were more likely to experience reactivation of viral RNA synthesis late after infection. Therefore, IFN-γ suppresses the local development of granzyme B-expressing CD8 + T cells and slows viral RNA clearance but promotes CD8 + T RM cell establishment.Viruses 2020, 12, 113 2 of 25 virus is no longer recoverable, but declining levels of viral RNA are still readily detectable. Finally, in Phase 3, from 60 days through at least a year and presumably for the life of the animal, viral RNA persists at a low level [10,11].The immune response to alphavirus infection in the CNS presents a double-edged sword: while local production of antibody and IFN-γ clears infectious virus [6-9], T cell-mediated inflammation is responsible for many of the pathological changes and much of the neurological damage produced [12][13][14]. CD8 + T cells participate in clearance of viral RNA because CD8 and B2m knockout mice clear viral RNA more slowly from the brains and spinal cords than wild-type (WT) mice [3].IFN-γ, an important product of natural killer (NK) cells and CD4 + and CD8 + T cells, exerts its antiviral effects by inducing IFN-stimulated genes (ISGs), but also by modulating the immune response to infection. The IFN-γ receptor is a heterotetramer of ligand-binding IFN-γR1 and signaling IFN-γR2 expressed on many cell types, including neurons [15]. IFN-γ binding to its receptor triggers a Jak/Stat signaling pathway that can induce expression of over 200 ISGs, some of which have direct antiviral activity, while others modulate the immune response [15][16][17]. IFN-γ is particularly important for clearance of infectious virus from spinal cord neurons [7]. IFN-γ-induced immunomodulatory effects include immune cell activation, trafficking, and differentiation, as well as more direct intracellular antiviral activities [18].IFN-γ is detectable in the CNS within 3 days after infection, peaks at 7 days and becomes undetectable by 10-14 days, although IFN-γ mRNA remains elevated for months [9]. Previous studies have shown that mice with impaired IFN-γ signaling produce lower levels of inflammatory cytokines and chemo...

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Section: Discussionmentioning

confidence: 99%

Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis

Baxter

Griffin

2020

Viruses

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“…After 1 h of infection, the inoculum was replaced with DMEM 1% penicillin-streptomycin and 2% FBS, supplemented with either DMSO, 2.5 µM benzavir-2, or 50 µM ribavirin. Supernatants were harvested at 24 hpi (TBEV and ZIKV) or 48 hpi (WNV, JEV, YFV, and DENV2), and titers were determined using focus-forming assay, as previously described [28,29]. In brief, viruses were diluted in 10-fold and used for infection of Vero B4 cells.…”

Section: Focus-forming Assay To Study Antiviral Compound Inhibitonmentioning

confidence: 99%

“…In brief, viruses were diluted in 10-fold and used for infection of Vero B4 cells. Viral foci were detected using primary monoclonal mouse antibodies, diluted by 1:1000, and directed against TBEV (19/1493) [30], flavivirus E (WNV, JEV, DENV2-HB112 ATCC), or YFV (CRC1689 ATCC) [29][30][31]. After primary antibody incubation, secondary horseradish peroxidase-conjugated anti-mouse antibodies (1:2000, Thermo Fisher Scientific) were added, followed by TrueBlue peroxidase substrate (KPL, Gaithersburg, MD, USA).…”

Section: Focus-forming Assay To Study Antiviral Compound Inhibitonmentioning

confidence: 99%

Antiviral Activity of Benzavir-2 against Emerging Flaviviruses

Gwon

Strand

Lindqvist

et al. 2020

Viruses

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Most flaviviruses are arthropod-borne viruses, transmitted by either ticks or mosquitoes, and cause morbidity and mortality worldwide. They are endemic in many countries and have recently emerged in new regions, such as the Zika virus (ZIKV) in South-and Central America, the West Nile virus (WNV) in North America, and the Yellow fever virus (YFV) in Brazil and many African countries, highlighting the need for preparedness. Currently, there are no antiviral drugs available to treat flavivirus infections. We have previously discovered a broad-spectrum antiviral compound, benzavir-2, with potent antiviral activity against both DNA-and RNA-viruses. Our purpose was to investigate the inhibitory activity of benzavir-2 against flaviviruses. We used a ZIKV ZsGreen-expressing vector, two lineages of wild-type ZIKV, and other medically important flaviviruses. Benzavir-2 inhibited ZIKV derived reporter gene expression with an EC 50 value of 0.8 ± 0.1 µM. Furthermore, ZIKV plaque formation, progeny virus production, and viral RNA expression were strongly inhibited. In addition, 2.5 µM of benzavir-2 reduced infection in vitro in three to five orders of magnitude for five other flaviviruses: WNV, YFV, the tick-borne encephalitis virus, Japanese encephalitis virus, and dengue virus. In conclusion, benzavir-2 was a potent inhibitor of flavivirus infection, which supported the broad-spectrum antiviral activity of benzavir-2.

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“…VeroB4 cells were cultured in medium 199/EBSS (Hyclone) supplemented with 10% FBS (Hyclone), 100 U/mL of penicillin and 100 µg/mL streptomycin (Gibco). Astrocytes and neurons were isolated and cultured as previously described [24,25]. In brief, astrocytes were isolated from cerebral cortices between postnatal day 1 and 4, seeded on poly-D-lysine (Sigma) coated T75 flasks and cultured in DMEM (Sigma) supplemented with 10% heat-inactivated FBS (Hyclone), 100 U/mL of penicillin and 100 µg/mL streptomycin (Gibco) and 2 mM L-glutamine (Gibco).…”

Section: Viruses and Cellsmentioning

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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Cell-type- and region-specific restriction of neurotropic flavivirus infection by viperin

Cited by 46 publications

References 54 publications

Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis

Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis

Antiviral Activity of Benzavir-2 against Emerging Flaviviruses

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

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