- Occupation-Associated Fatal Limbic Encephalitis Caused by Variegated Squirrel Bornavirus 1, Germany, 2013. [Journal Article]
- EIEmerg Infect Dis 2018; 24(6):978-987
- Limbic encephalitis is commonly regarded as an autoimmune-mediated disease. However, after the recent detection of zoonotic variegated squirrel bornavirus 1 in a Prevost's squirrel (Callosciurus prev...
Limbic encephalitis is commonly regarded as an autoimmune-mediated disease. However, after the recent detection of zoonotic variegated squirrel bornavirus 1 in a Prevost's squirrel (Callosciurus prevostii) in a zoo in northern Germany, we retrospectively investigated a fatal case in an autoantibody-seronegative animal caretaker who had worked at that zoo. The virus had been discovered in 2015 as the cause of a cluster of cases of fatal encephalitis among breeders of variegated squirrels (Sciurus variegatoides) in eastern Germany. Molecular assays and immunohistochemistry detected a limbic distribution of the virus in brain tissue of the animal caretaker. Phylogenetic analyses demonstrated a spillover infection from the Prevost's squirrel. Antibodies against bornaviruses were detected in the patient's cerebrospinal fluid by immunofluorescence and newly developed ELISAs and immunoblot. The putative antigenic epitope was identified on the viral nucleoprotein. Other zoo workers were not infected; however, avoidance of direct contact with exotic squirrels and screening of squirrels are recommended.
- Postherpes simplex encephalitis: a case series of viral-triggered autoimmunity, synaptic autoantibodies and response to therapy. [Journal Article]
- TATher Adv Neurol Disord 2018; 11:1756286418768778
- Recent evidence suggests that patients with herpes simplex virus (HSV) encephalitis may relapse because of autoimmunity against the N-methyl-D-aspartate receptor (NMDAR). We present a case series of ...
Recent evidence suggests that patients with herpes simplex virus (HSV) encephalitis may relapse because of autoimmunity against the N-methyl-D-aspartate receptor (NMDAR). We present a case series of post-HSV relapsing encephalopathy associated with antibodies to central nervous system (CNS) synaptic antigens.
- Protein Phosphatase 1α Interacts with Venezuelan Equine Encephalitis Virus Capsid Protein and Regulates Viral Replication through Modulation of Capsid Phosphorylation. [Journal Article]
- JVJ Virol 2018 May 16
- Protein Phosphatase 1 (PP1) is a serine/threonine phosphatase which has been implicated in the regulation of a number of viruses including HIV-1, Ebolavirus and Rift Valley fever virus. Catalytic sub...
Protein Phosphatase 1 (PP1) is a serine/threonine phosphatase which has been implicated in the regulation of a number of viruses including HIV-1, Ebolavirus and Rift Valley fever virus. Catalytic subunits of PP1 (PP1α, PP1β, or PP1γ) interact with a host of regulatory subunits and target a wide variety of cellular substrates through a combination of short binding motifs, including an RVxF motif present in the majority of PP1 regulatory subunits. Targeting the RVxF interacting site on PP1 with the small molecule, 1E7-03 inhibits HIV-1, Ebolavirus, and Rift Valley fever virus replication. Here we determined the effect of PP1 on Venezuelan equine encephalitis virus (VEEV) replication. Treatment of VEEV infected cells with 1E7-03 decreased viral replication by over 2 logs (EC50=0.6 μM). 1E7-03 treatment reduced viral titers starting at 8 hours post infection. Viral replication was also decreased after treatment with PP1α-targeting siRNA. Confocal microscopy demonstrated that PP1α shuttles toward the cytosol during infection with VEEV and that PP1α colocalizes with VEEV capsid. Co-immunoprecipitation experiments confirmed VEEV capsid interacting with PP1α. Furthermore, immunoprecipitation and mass spectrometry data showed that VEEV capsid is phosphorylated and that phosphorylation is moderated by PP1α. Finally, less viral RNA is associated with capsid after treatment with 1E7-03. Coupled with data that shows 1E7-03 inhibits several alphaviruses, this study indicates that inhibition of the PP1α RVxF binding pocket is a promising therapeutic target and provides novel evidence that PP1α modulation of VEEV capsid phosphorylated influences viral replication.ImportanceVenezuelan equine encephalitis virus (VEEV) causes moderate flu-like symptoms and can lead to severe encephalitic disease and potentially death. There are no currently FDA approved therapeutics or vaccines for human use and understanding the molecular underpinning of host:virus interactions can aid in the rational design of intervention strategies. The significance of our research is in identifying the interaction between Protein Phosphatase 1 (PP1) and the viral capsid protein. This interaction is important for viral replication as inhibition of PP1 results in decrease viral replication. Inhibition of PP1 also inhibited multiple biomedically important alphaviruses, indicating PP1 may be a potential therapeutic target for alphavirus induced disease.
- The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport. [Journal Article]
- IImmunity 2018 May 15; 48(5):911-922.e7
- Unc-93 homolog B1 (UNC93B1) is a key regulator of nucleic acid (NA)-sensing Toll-like receptors (TLRs). Loss of NA-sensing TLR responses in UNC93B1-deficient patients facilitates Herpes simplex virus...
Unc-93 homolog B1 (UNC93B1) is a key regulator of nucleic acid (NA)-sensing Toll-like receptors (TLRs). Loss of NA-sensing TLR responses in UNC93B1-deficient patients facilitates Herpes simplex virus type 1 (HSV-1) encephalitis. UNC93B1 is thought to guide NA-sensing TLRs from the endoplasmic reticulum (ER) to their respective endosomal signaling compartments and to guide the flagellin receptor TLR5 to the cell surface, raising the question of how UNC93B1 mediates differential TLR trafficking. Here, we report that UNC93B1 regulates a step upstream of the differential TLR trafficking process. We discovered that UNC93B1 deficiency resulted in near-complete loss of TLR3 and TLR7 proteins in primary splenic mouse dendritic cells and macrophages, showing that UNC93B1 is critical for maintaining TLR expression. Notably, expression of an ER-retained UNC93B1 version was sufficient to stabilize TLRs and largely restore endosomal TLR trafficking and activity. These data are critical for an understanding of how UNC93B1 can regulate the function of a broad subset of TLRs.
- Dual TLR2/9 Recognition of Herpes Simplex Virus Infection Is Required for Recruitment and Activation of Monocytes and NK Cells and Restriction of Viral Dissemination to the Central Nervous System. [Journal Article]
- FIFront Immunol 2018; 9:905
- The importance of TLR2 and TLR9 in the recognition of infection with herpes simplex virus (HSV) and HSV-caused diseases has been described, but some discrepancies remain concerning the benefits of th...
The importance of TLR2 and TLR9 in the recognition of infection with herpes simplex virus (HSV) and HSV-caused diseases has been described, but some discrepancies remain concerning the benefits of these responses. Moreover, the impact of TLR2/9 on innate and adaptive immune responses within relevant mucosal tissues has not been elucidated using natural mucosal infection model of HSV. Here, we demonstrate that dual TLR2/9 recognition is essential to provide resistance against mucosal infection with HSV via an intravaginal route. Dual TLR2/9 ablation resulted in the highly enhanced mortality with exacerbated symptoms of encephalitis compared with TLR2 or TLR9 deficiency alone, coinciding with highly increased viral load in central nervous system tissues. TLR2 appeared to play a minor role in providing resistance against mucosal infection with HSV, since TLR2-ablated mice showed higher survival rate compared with TLR9-ablated mice. Also, the high mortality in dual TLR2/9-ablated mice was closely associated with the reduction in early monocyte and NK cell infiltration in the vaginal tract (VT), which was likely to correlate with low expression of cytokines and CCR2 ligands (CCL2 and CCL7). More interestingly, our data revealed that dual TLR2/9 recognition of HSV infection plays an important role in the functional maturation of TNF-α and iNOS-producing dendritic cells (Tip-DCs) from monocytes as well as NK cell activation in VT. TLR2/9-dependent maturation of Tip-DCs from monocytes appeared to specifically present cognate Ag, which effectively provided functional effector CD4+ and CD8+ T cells specific for HSV Ag in VT and its draining lymph nodes. TLR2/9 expressed in monocytes was likely to directly facilitate Tip-DC-like features after HSV infection. Also, dual TLR2/9 recognition of HSV infection directly activated NK cells without the aid of dendritic cells through activation of p38 MAPK pathway. Taken together, these results indicate that dual TLR2/9 recognition plays a critical role in providing resistance against mucosal infection with HSV, which may involve a direct regulation of Tip-DCs and NK cells in VT. Therefore, our data provide a more detailed understanding of TLR2/9 role in conferring antiviral immunity within relevant mucosal tissues after mucosal infection with HSV.
- Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity. [Journal Article]
- JIJ Immunol 2018 May 14
- Tick-borne encephalitis virus (TBEV) is one of the flaviviruses that targets the CNS and causes encephalitis in humans. The mechanism of TBEV that causes CNS destruction remains unclear. It has been ...
Tick-borne encephalitis virus (TBEV) is one of the flaviviruses that targets the CNS and causes encephalitis in humans. The mechanism of TBEV that causes CNS destruction remains unclear. It has been reported that RANTES-mediated migration of human blood monocytes and T lymphocytes is specifically induced in the brain of mice infected with TBEV, which causes ensuing neuroinflammation and may contribute to brain destruction. However, the viral components responsible for RANTES induction and the underlying mechanisms remain to be fully addressed. In this study, we demonstrate that the NS5, but not other viral proteins of TBEV, induces RANTES production in human glioblastoma cell lines and primary astrocytes. TBEV NS5 appears to activate the IFN regulatory factor 3 (IRF-3) signaling pathway in a manner dependent on RIG-I/MDA5, which leads to the nuclear translocation of IRF-3 to bind with RANTES promoter. Further studies reveal that the activity of RNA-dependent RNA polymerase (RdRP) but not the RNA cap methyltransferase is critical for TBEV NS5-induced RANTES expression, and this is likely due to RdRP-mediated synthesis of dsRNA. Additional data indicate that the residues at K359, D361, and D664 of TBEV NS5 are critical for RdRP activity and RANTES induction. Of note, NS5s from other flaviviruses, including Japanese encephalitis virus, West Nile virus, Zika virus, and dengue virus, can also induce RANTES expression, suggesting the significance of NS5-induced RANTES expression in flavivirus pathogenesis. Our findings provide a foundation for further understanding how flaviviruses cause neuroinflammation and a potential viral target for intervention.
- Multicenter phase 1/2 application of adenovirus-specific T cells in high-risk pediatric patients after allogeneic stem cell transplantation. [Journal Article]
- CCytotherapy 2018 May 09
- CONCLUSIONS: The study demonstrates the safety and feasibility of pre-emptively manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation and provides early evidence of clinical efficacy.
- Status epilepticus associated with acute encephalitis: long-term follow-up of functional and cognitive outcomes in 72 patients. [Journal Article]
- EJEur J Neurol 2018 May 11
- CONCLUSIONS: Survival with favorable functional recovery was promising after prolonged RSE in patients with acute encephalitis. This article is protected by copyright. All rights reserved.
- Genotype I of Japanese Encephalitis Virus Virus-like Particles Elicit Sterilizing Immunity against Genotype I and III Viral Challenge in Swine. [Journal Article]
- SRSci Rep 2018 May 10; 8(1):7481
- Swine are a critical amplifying host involved in human Japanese encephalitis (JE) outbreaks. Cross-genotypic immunogenicity and sterile protection are important for the current genotype III (GIII) vi...
Swine are a critical amplifying host involved in human Japanese encephalitis (JE) outbreaks. Cross-genotypic immunogenicity and sterile protection are important for the current genotype III (GIII) virus-derived vaccines in swine, especially now that emerging genotype I (GI) JE virus (JEV) has replaced GIII virus as the dominant strain. Herein, we aimed to develop a system to generate GI JEV virus-like particles (VLPs) and evaluate the immunogenicity and protection of the GI vaccine candidate in mice and specific pathogen-free swine. A CHO-heparan sulfate-deficient (CHO-HS(-)) cell clone, named 51-10 clone, stably expressing GI-JEV VLP was selected and continually secreted GI VLPs without signs of cell fusion. 51-10 VLPs formed a homogeneously empty-particle morphology and exhibited similar antigenic activity as GI virus. GI VLP-immunized mice showed balanced cross-neutralizing antibody titers against GI to GIV viruses (50% focus-reduction micro-neutralization assay titers 71 to 240) as well as potent protection against GI or GIII virus infection. GI VLP-immunized swine challenged with GI or GIII viruses showed no fever, viremia, or viral RNA in tonsils, lymph nodes, and brains as compared with phosphate buffered saline-immunized swine. We thus conclude GI VLPs can provide sterile protection against GI and GIII viruses in swine.
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- Complete Genomic Characterization of Three Tick-Borne Encephalitis Viruses Detected Along the China-North Korea Border, 2011. [Journal Article]
- VBVector Borne Zoonotic Dis 2018 May 09
- Tick-borne encephalitis virus (TBEV) causes neurological infections with serious sequelae in Europe and Northeast Asia. In China, the major epidemic areas are along the borders with Russia and North ...
Tick-borne encephalitis virus (TBEV) causes neurological infections with serious sequelae in Europe and Northeast Asia. In China, the major epidemic areas are along the borders with Russia and North Korea. Although several TBEV isolates have been reported, the biological characteristics of the Chinese strains, especially those along the China-North Korea border, are unclear. In this study, we detected seven TBEV fragment sequences in 602 adult Dermacentor silvarum collected in the Changbai Mountain area of Jilin Province on the China-North Korea border and characterized the genome of three TBEV strains (JLCB11-08, JLCB11-35, and JLCB11-40). These three TBEV strains belong to the TBEV-Far Eastern (TBEV-FE) genotype and clustered most closely with the Svetlogorie and Kavalerovo strains from Russia. In addition, the TBEV strains from Northeast China clustered geographically within the TBEV-FE subtype branch. These findings will facilitate further research on the distinct genetic groupings of TBEV strains in China.