RARE DISEASE
Borna virus encephalitis
Borna virus encephalitis
Borna virus encephalitis
Synonyms: Bornavirus encephalitis
Synonyms: Bornavirus encephalitis
Synonyms: Bornavirus encephalitis
Drug discovery
72
papers
On emerging therapies
Overview
Borna Virus Encephalitis Overview
Borna virus encephalitis, caused by the neurotropic BoDV-1, is a rare, severe zoonosis transmitted via the bicolored white-toothed shrew. It presents with nonspecific prodromal symptoms (fever, headache) followed by rapid neurological decline, including altered consciousness, brainstem dysfunction, and coma. Mortality exceeds 90%, with no proven therapies. Diagnosis relies on CSF PCR, serology, or postmortem brain biopsy showing lymphocytic panencephalomyelitis and eosinophilic intranuclear inclusions [1][6][9][13].
Categories: rare infectious diseases, rare neurological diseases
Research Papers
72 drug discovery papers about Borna virus encephalitis. Recent publications:
72 drug discovery papers about Borna virus encephalitis. Recent publications:
categories:
Small molecules
small molecules
2026-05-29 | Structural mechanism of Borna disease virus 1 RNA polymerase autoinhibition and suramin-mediated inhibition.
Borna disease virus 1 (BoDV-1) is a neurotropic pathogen that causes severe, often fatal encephalitis, yet effective treatments remain unavailable. As a nuclear-replicating mononegavirus, BoDV-1 employs a minimal L-P polymerase complex. Here, we report cryo-electron microscopy (cryo-EM) structures of the BoDV-1 polymerase in L-alone, apo-L-P, and inhibitor-bound L-P states, revealing the most compact L protein characterized among mononegaviruses. While the catalytic core is conserved, the C-terminal domains are degenerate, with the methyltransferase-like (MTase-like) domain lacking canonical functional motifs. We identify an N-terminal autoinhibitory element (AIE) that is positioned to physically block the template entry tunnel, suggesting an autoinhibition mechanism reminiscent of a "molecular plug." Furthermore, we demonstrate that the inhibitor suramin binds in a specific triple-molecule mode, potentially achieving inhibition by sterically occluding RNA access and allosterically restricting the catalytic core. These findings elucidate the architecture and regulation of the BoDV-1 polymerase, providing a structural framework for rational antiviral design.
2026-05-14 | Multimodal profiling of immune responses reveals innate-adaptive immune imbalance in human bornavirus encephalitis
Abstract Human bornavirus encephalitis (BVE) is a rare, emerging and fatal zoonotic disease mainly caused by the Borna disease virus 1 (BoDV-1), a non-cytolytic RNA virus. Despite increasing recognition, the immunopathogenesis of human BoDV-1 infection remains insufficiently characterised. Complete coronal and sagittal brain sections from four fatal BoDV-1 cases were analysed using digitised immunohistochemistry to quantify viral distribution and tissue responses. Transcriptome-based analyses characterised local immune cell profiles in relation to viral loads measured by RT-qPCR. BoDV-1 viral loads varied substantially between cases but showed region-specific enrichment in the basal ganglia and hippocampus, correlating with lymphocyte presence and reactive microglia and astrocytes. Immune cell deconvolution revealed viral load-dependent modulation dominated by innate immune and glial populations, including metabolic and reactive astrocyte states, IFNγ-responsive microglia, and dendritic cells, macrophages, neutrophils, basophils, and CD8⁺ T cells. This was accompanied by induction of interferon-stimulated genes, antigen presentation, protein synthesis, and oxidative stress pathways, with a transcriptional signature resembling non-lytic viral and autoimmune-like neuroinflammatory conditions rather than lytic infections. These findings support a model of BoDV-1 encephalitis characterised by a prominent innate immune response and comparatively limited adaptive immune signatures. This imbalance might potentially contribute to impaired viral clearance and extensive tissue damage, a possible relationship that warrants further investigation.
2025-10-05 | First therapeutic drug monitoring of experimental favipiravir in Borna disease virus 1 (BoDV-1) encephalitis patients reveals significant gaps in antiviral treatment: a pilot investigation.
The Borna disease virus 1 (BoDV-1) causes a rare, but severe form of encephalitis in Germany, characterized by rapid progression, late diagnosis, and a high case fatality. Therapy is experimental and recommendations are lacking. Favipiravir (FPV) suppresses BoDV-1 replication in vitro and has been used in a handful of BoDV-1 patients within individual treatment attempts, but little is known about the drug´s pharmacokinetics in encephalitis. To monitor and therefore optimize experimental FPV treatment, we established a liquid chromatography tandem mass spectroscopy (LC-MS/MS) assay for serum and cerebrospinal fluid (CSF), and analyzed stored specimens of two patients with BoDV-1 encephalitis in the context of therapeutic drug monitoring as a pilot investigation. We demonstrate for the first time that orally administered FPV reaches the CSF in BoDV-1 encephalitis. However, the half-maximal inhibitory concentration (IC50) for BoDV-1 was met only in one patient, raising questions on significantly higher dosing and/or alternative formulations for effective treatment. In conclusion, monitoring experimental FPV therapy in BoDV-1 encephalitis is feasible and should be performed continuously. Future prospective in-depth (multicenter) studies should include more patients and focus on dose-finding, dose-response relationships, and define a therapeutic index to improve outcomes of this so far nearly uniformly fatal disease.
2025-09-25 | Structural insights into the dynamic mechanism of bornavirus polymerase.
Borna disease virus 1 (BoDV-1), an emerging zoonotic pathogen from the Bornaviridae family, is neurotropic and can infect a variety of mammalian hosts, including humans. Linked to severe encephalitis and high mortality, BoDV-1 currently lacks licensed treatments or vaccines. The BoDV-1 polymerase complex, comprising the large (L) and phosphoprotein (P) subunits, is crucial for viral replication and transcription, making it a promising target for antiviral intervention. Here, we present the cryoelectron microscopy structure of the apo BoDV-1 L-P complex, revealing a unique "mitten-shaped" architecture. The structure characterizes key domains involved in RNA synthesis, including RNA-dependent RNA polymerase, polyribonucleotidyltransferase, and an inactive methyltransferase domain. While no RNA or NTPs were visible, we observed distinct conformational states, showing large-scale rearrangements of the P tetramer and L domains, as well as remodeling of the RNA template, nucleoside triphosphates, and nascent RNA entrances and/or exits, upon introducing RNA and NTPs. These findings highlight the dynamic structural changes probably associated with polymerase activity and advance the understanding of the BoDV-1 polymerase mechanisms, offering a basis for developing targeted antiviral strategies against this deadly pathogen.
2025-08-04 | Demographic data on included humans and animals.
Borna disease virus 1 (BoDV-1) has long been recognized as a cause of fatal encephalitis in animals and was only recently identified as a zoonotic pathogen causing a similar disease in humans. This study provides the first comprehensive comparative analysis of BoDV-1-induced neuropathology in human and animal end hosts, including horses, sheep, and alpacas. Using immunohistochemical analyses, we investigated the topographical distribution of BoDV-1 and inflammatory responses in the central nervous system across 19 cases. Key findings reveal distinct differences and overlaps between humans and animals. While humans exhibited heterogeneous patterns especially of the lymphocyte infiltration, animals displayed more species-specific inflammation and viral spread patterns. In horses, the hippocampus and basal ganglia were consistently affected, whereas sheep showed predominant involvement of the frontal cortex and stria olfactoria. Alpacas demonstrated a less uniform distribution but highlighted the brainstem and basal ganglia as critical sites. Intriguingly, across all species, a negative association was observed between lymphocyte infiltration and the number of BoDV-1-infected cells. These findings enhance our understanding of BoDV-1 pathogenesis and is a first step of cross-species comparison in unraveling disease mechanisms in BoDV-1 infection. Further research is warranted to elucidate the implications of these findings for therapeutic strategies and to explore the entry and dissemination routes of BoDV-1 in different hosts.
antibodies
2026-08-13 | Long-Term Survival of Borna Disease Virus 1 (BoDV-1)-Encephalitis: An Exceptional Case with Valuable Insights for Pathophysiology and Disease Management.
Borna disease virus 1 (BoDV-1) encephalitis has a (sub)acute and mostly fatal course. Initial flu-like symptoms are typically followed by rapid progressive panencephalitis and death within weeks. No curative therapy exists so far. We present a long-term survivor with distinctive clinical, imaging, and pathophysiological features. A previously healthy male in his fifties was admitted in summer 2023 with (sub)acute encephalitis (cerebrospinal fluid, CSF: 132 cells/µl, no pathogen detection). Brain magnetic resonance imaging (MRI) demonstrated vasogenic edema affecting basal ganglia, temporal and limbic regions bilaterally. Despite high-dose steroids, the clinical condition of the patient slowly worsened. Three months later, BoDV-1 reactive antibodies were detected by elevated titers in CSF (1:320) and serum (1:5120). Treatment with favipiravir, corticosteroids, and mycophenolate mofetil (MMF) was initiated. After recovery for months, the patient developed progressive bilateral optic atrophy, cognitive decline, and a sleep disorder resembling Kleine-Levin syndrome. Translocator protein (TSPO)-PET revealed widespread microglial activation, confirmed by targeted cortical biopsy. Immunosuppressive therapy was escalated with anakinra, cyclophosphamide, and intrathecal dexamethasone, achieving temporary stabilization. In the summer of 2025, a severe brainstem syndrome emerged, accompanied by increased TSPO uptake in the brainstem and detection of BoDV-1 RNA in CSF for the first time. Despite another treatment with favipiravir and high-dose corticosteroids, the patient remained in a minimally conscious state. This exceptional case with long-term survival in BoDV-1 encephalitis gives important insights: BoDV1-associated neuroinflammation leading to a slowly progressive decline can be visualized by TSPO-PET. Late BoDV-1 RNA detection and subacute re-exacerbation after prolonged survival provides evidence that BoDV-1 persists in human brain tissue.
2001-01-15 | Neutralizing Antibodies in Persistent Borna Disease Virus Infection: Prophylactic Effect of gp94-Specific Monoclonal Antibodies in Preventing Encephalitis
Borna disease virus (BDV) infection triggers an immune-mediated encephalomyelitis and results in a persistent infection. The immune response in the acute phase of the disease is characterized by a cellular response in which CD8(+) T cells are responsible for the destruction of virus-infected brain cells. CD4(+) T cells function as helper cells and support the production of antiviral antibodies. Antibodies generated in the acute phase of the disease against the nucleoprotein and the phosphoprotein are nonneutralizing. In the chronic phase of the disease, neutralizing antibodies directed against the matrix protein and glycoprotein are synthesized. In the present work, the biological role of the neutralizing-antibody response to BDV was further investigated. By analyzing the blood of rats infected intracerebrally with BDV, a highly neurotropic virus, nucleic acid could be detected between 30 and 50 days after infection. Neutralizing antibodies were found between 60 and 100 days after infection. Furthermore, we produced hybridomas secreting BDV-specific neutralizing monoclonal antibodies. These antibodies, directed against the major glycoprotein (gp94) of BDV, were able to prevent Borna disease if given prophylactically. These data suggest that the late appearance of BDV-specific neutralizing antibodies is due to the presence of BDV in the blood of chronically infected rats. Furthermore, these antibodies have the potential to neutralize the infectious virus when given early, which is an important finding with respect to the development of a vaccine.
1998-06-25 | In vivo treatment with anti-alpha4 integrin suppresses clinical and pathological evidence of Borna disease virus infection.
Borna disease virus (BDV) infection of the rat brain induces a severe T-lymphocyte mediated inflammatory response that parallels the course of clinical Borna disease. In other models of CNS inflammation, the recruitment of T-lymphocytes from the circulation to sites of inflammation is believed to be directed, in part, by the cellular adhesion molecules alpha4 beta1 integrin (expressed on T-lymphocytes) and its ligand VCAM-1 (expressed on blood brain barrier endothelium). Since BDV-specific T-lymphocytes are known to express the alpha4 beta1 integrin, we examined the effect of in vivo treatment with an anti-alpha4 integrin monoclonal antibody (GG5/3) on the development of BDV-specific encephalitis and Borna disease. Here, we report that the inhibition of alpha4 integrin provided significant clinical benefit in slowing the progression of Borna disease. Antibody treatment greatly reduced the immune cell infiltrates in the CNS of BDV-infected animals, but we found that this inhibition of the immune response did not result in enhanced viral levels.
1993-12-09 | Brain cell lesions in Borna disease are mediated by T cells.
Experimental Borna Disease (BD) in rats is characterized by severe lymphocytic encephalitis and by massive brain cell lesions finally leading to brain atrophy. Treatment of BDV-infected rats with monoclonal antibodies directed against CD4+ and CD8+ T cells could almost completely inhibit the immunopathological reactions and revealed less BDV-infected neurons and astrocytes that expressed MHC class I antigen. Brain cell lesions were minimal, and no obvious brain atrophy could be observed even late after infection. Since BDV itself is not known to exert cytopathic effects and since brain cell damage was independent of antibody titers, brain cell destruction correlates well with the intracerebral presence of CD8+ T cells and the expression of MHC class I antigens. Moreover, BDV-infected brain cells in vitro could be demonstrated to be lysed in a MHC class I-restricted manner. These findings provide evidence that virus-infected neurons can be destructed by T cell mediated cytotoxicity which results in organ atrophy and dementia.
1992-06-16 | Preventive effects of early anti-CD4 or anti-CD8 treatment on Borna disease in rats.
Borna disease is a virus-induced, immunopathological encephalomyelitis in which CD4+ cells and macrophages dominate the pathological picture. However, significant numbers of CD8+ cells have been morphologically identified in perivascular infiltrates as well. To determine the contribution of different T-cell subsets to the pathogenesis of Borna disease, virus-infected rats were treated with monoclonal antibodies specific for CD4+ and CD8+ cells. Both types of monoclonal antibodies were able to significantly decrease or even prevent the local inflammatory reaction in the brain if given early during the infection. However, CD8-specific monoclonal antibodies appeared to be more effective than antibodies directed against CD4+ cells. Treatment initiated 4 days postinfection did not result in inhibition of encephalitis and disease. Virus titers in the brain of infected rats treated with T-cell-specific antibodies did not differ from titers in untreated infected control animals. The results indicate an important functional role of CD8+ cells, in addition to CD4+ cells, in the pathogenesis of Borna disease.
vaccines
2025-10-13 | Is vaccination a feasible public health strategy against fatal Borna disease virus 1 (BoDV-1) encephalitis? An epidemiological perspective.
Human Borna disease virus 1 (BoDV-1) encephalitis is characterized by rapid clinical progression, an absence of a causal therapy and an extremely high case fatality rate. Here, we discuss prevention options through a hypothetical vaccine focusing on epidemiological features.
2024-12-20 | Developing a universal multi-epitope protein vaccine candidate for enhanced borna virus pandemic preparedness.
Borna disease virus 1 (BoDV-1) is an emerging zoonotic RNA virus that can cause severe acute encephalitis with high mortality. Currently, there are no effective countermeasures, and the potential risk of a future outbreak requires urgent attention. To address this challenge, the complete genome sequence of BoDV-1 was utilized, and immunoinformatics was applied to identify antigenic peptides suitable for vaccine development. Immunoinformatics and antigenicity-focused protein screening were employed to predict B-cell linear epitopes, B-cell conformational epitopes, and cytotoxic T lymphocyte (CTL) epitopes. Only overlapping epitopes with antigenicity greater than 1 and non-toxic, non-allergenic properties were selected for subsequent vaccine construction. The epitopes were linked using GPGPG linkers, incorporating β-defensins at the N-terminus to enhance immune response, and incorporating Hit-6 at the C-terminus to improve protein solubility and aid in protein purification. Computational tools were used to predict the immunogenicity, physicochemical properties, and structural stability of the vaccine. Molecular docking was performed to predict the stability and dynamics of the vaccine in complex with Toll-like receptor 4 (TLR-4) and major histocompatibility complex I (MHC I) receptors. The vaccine construct was cloned through in silico restriction to create a plasmid for expression in a suitable host. Among the six BoDV-1 proteins analyzed, five exhibited high antigenicity scores. From these, eight non-toxic, non-allergenic overlapping epitopes with antigenicity scores greater than 1 were selected for vaccine development. Computational predictions indicated favorable immunogenicity, physicochemical properties, and structural stability. Molecular docking analysis showed that the vaccine remained stable in complex with TLR-4 and MHC I receptors, suggesting strong potential for immune recognition. A plasmid construct was successfully generated, providing a foundation for the experimental validation of vaccines in future pandemic scenarios. These findings demonstrate the potential of the immunoinformatics-designed multi-epitope vaccines for the prevention and treatment of BoDV-1. Relevant preparations were made in advance for possible future outbreaks and could be quickly utilized for experimental verification.
2022-12-26 | Vaccination against Borna Disease: Overview, Vaccine Virus Characterization and Investigation of Live and Inactivated Vaccines.
(1) Background: Vaccination of horses and sheep against Borna disease (BD) was common in endemic areas of Germany in the 20th century but was abandoned in the early 1990s. The recent occurrence of fatal cases of human encephalitis due to Borna disease virus 1 (BoDV-1) has rekindled the interest in vaccination. (2) Methods: The full genomes of the BD live vaccine viruses "Dessau" and "Giessen" were sequenced and analyzed for the first time. All vaccination experiments followed a proof-of-concept approach. Dose-titration infection experiments were performed in rabbits, based on both cell culture- and brain-derived viruses at various doses. Inactivated vaccines against BD were produced from concentrated cell culture supernatants and investigated in rabbits and horses. The BoDV-1 live vaccine "Dessau" was administered to horses and antibody profiles were determined. (3) Results: The BD live vaccine viruses "Dessau" and "Giessen" belong to clusters 3 and 4 of BoDV-1. Whereas the "Giessen" virus does not differ substantially from field viruses, the "Dessau" virus shows striking differences in the M gene and the N-terminal part of the G gene. Rabbits infected with high doses of cell-cultured virus developed neutralizing antibodies and were protected from disease, whereas rabbits infected with low doses of cell-cultured virus, or with brain-derived virus did not. Inactivated vaccines were administered to rabbits and horses, following pre-defined vaccination schemes consisting of three vaccine doses of either adjuvanted or nonadjuvanted inactivated virus. Their immunogenicity and protective efficacy were compared to the BD live vaccine "Dessau". Seventy per cent of horses vaccinated with the BD live vaccine "Dessau" developed neutralizing antibodies after vaccination. (4) Conclusion: Despite a complex evasion of immunological responses by bornaviruses, some vaccination approaches can protect against clinical disease. For optimal effectiveness, vaccines should be administered at high doses, following vaccination schemes consisting of three vaccine doses as basic immunization. Further investigations are necessary in order to investigate and improve protection against infection and to avoid side effects.
2005-01-19 | Vaccine-induced protection against Borna disease in wild-type and perforin-deficient mice
Borna disease virus (BDV) can persistently infect the central nervous system and induce CD8 + T-cell-mediated neurological disease in MRL mice. To determine whether specific immune priming would prevent disease, a prime–boost immunization protocol was established in which intramuscular injection of a recombinant parapoxvirus expressing BDV nucleoprotein (BDV-N) was followed by intraperitoneal infection with vaccinia virus expressing BDV-N. Immunized wild-type and perforin-deficient mice remained healthy after intracerebral infection with BDV and contained almost no virus in the brain at 5 weeks post-challenge. Immunization failed to induce resistance against BDV in mice lacking mature CD8 + T cells. Immunization of perforin-deficient mice with a poxvirus vector expressing mutant BDV-N lacking the known CD8 + T-cell epitope did not efficiently block multiplication of BDV in the brain and did not prevent neurological disease, indicating that vaccine-induced immunity to BDV in wild-type and perforin-deficient mice resulted from the action of CD8 + T cells.
2001-12-01 | High-Dose Borna Disease Virus Infection Induces a Nucleoprotein-Specific Cytotoxic T-Lymphocyte Response and Prevention of Immunopathology
ABSTRACT Experimental Borna disease virus (BDV) infection of rats and natural infection of horses and sheep leads to severe central nervous system disease based on immunopathological pathways. The virus replicates slowly, and the cellular immune response results in immunopathology. CD8 + T cells exert effector cell functions, and their activity results in the destruction of virus-infected cells. Previously, Oldach and colleagues (D. Oldach, M. C. Zink, J. M. Pyper, S. Herzog, R. Rott, O. Narayan, and J. E. Clements, Virology 206:426–434, 1995) have reported protection against Borna disease after inoculation of high-dose cell-adapted BDV. Here we show that the outcome of the infection, i.e., immunopathology versus protection, is simply dependent on the amount of virus used for infection. High-dose BDV (10 6 FFU) triggers an early virus-specific reaction of the immune system, as demonstrated by strong cellular and humoral responses. In particular, the early presence and function of nucleoprotein-specific CD8 + T cells could be demonstrated in the brain. We present evidence that in a noncytolytic and usually persistent virus infection, high-dose input virus mediates early control of the pathogen due to an efficient induction of an antiviral immune mechanism. From these data, we conclude that immune reactivity, in particular the cytotoxic T-cell response, determines whether the virus is controlled with prevention of the ensuing immunopathological disease or whether a persistent infection is established.
gene therapies
2024-04-15 | The absence of superinfection exclusion of Borna disease virus 2 maintains genomic polymorphisms in persistently infected cells
Abstract Viruses belonging to the genus Orthobornavirus within the family Bornaviridae are known to infect various vertebrate species, including mammals and birds. Within the genus, the species Orthobornavirus bornaense includes two mammalian viruses: Borna disease virus 1 (BoDV-1), the prototype of the family, and its closely related virus, BoDV-2. BoDV-1 was identified as the causative agent of Borna disease (BD) in horses, sheep, humans, and other mammals. BoDV-2 was first detected in a pony in eastern Austria in 1999 that exhibited severe and incurable neurological symptoms. Although BoDV-2 shares approximately 80% nucleotide identity with BoDV-1, its virological properties, including host range, replication ability, and pathogenicity, remain unclear. In this study, we aimed to investigate the virological properties of BoDV-2 by re-evaluating its whole-genome sequence using RNA sequencing. Compared to the published reference sequence, we identified two nonsynonymous nucleotide substitutions in the large (L) gene. One of these substitutions was found to be critical for the restoration of polymerase activity, enabling the successful recovery of recombinant BoDV-2 (rBoDV-2) through reverse genetics. We also identified two nonsynonymous single-nucleotide polymorphisms (SNPs) in the L gene and one in the phosphoprotein (P) gene. Substitution of these SNPs significantly enhanced the growth ability of rBoDV-2. In addition, our studies showed that BoDV-2 does not induce superinfection exclusion in cells, allowing persistence of low-fitness genome variants for an extended period of time. These findings help to characterize the virological properties of BoDV-2 and shed light on how bornaviruses maintain genetic diversity in infected cells. Importance Mammalian bornaviruses are a general term for viruses belonging to the genus Orthobornavirus that infect mammalian species, e.g., Borna disease virus 1 and 2 (BoDV-1 and -2) and variegated squirrel bornavirus 1 (VSBV-1). Although BoDV-1 and VSBV-1 are reported to be associated with fatal encephalitis in humans, the infectivity and pathogenicity of BoDV-2 in humans remain unclear. To determine the virological properties of BoDV-2, we developed a reverse genetics system for BoDV-2. By using recombinant BoDV-2s, we identified several nucleotides that affect the growth ability of BoDV-2 and revealed the molecular mechanisms through which BoDV-2 maintains genetic heterogeneity in persistently infected cells. This reverse genetics system will accelerate the biological studies of BoDV-2 and contribute to the development of countermeasures against mammalian bornaviruses.
2024-03-20 | Suppression of Borna Disease Virus Replication during Its Persistent Infection Using the CRISPR/Cas13b System
Borna disease virus (BoDV-1) is a bornavirus that infects the central nervous systems of various animal species, including humans, and causes fatal encephalitis. BoDV-1 also establishes persistent infection in neuronal cells and causes neurobehavioral abnormalities. Once neuronal cells or normal neural networks are lost by BoDV-1 infection, it is difficult to regenerate damaged neural networks. Therefore, the development of efficient anti-BoDV-1 treatments is important to improve the outcomes of the infection. Recently, one of the clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) systems, CRISPR/Cas13, has been utilized as antiviral tools. However, it is still unrevealed whether the CRISPR/Cas13 system can suppress RNA viruses in persistently infected cells. In this study, we addressed this question using persistently BoDV-1-infected cells. The CRISPR/Cas13 system targeting viral mRNAs efficiently decreased the levels of target viral mRNAs and genomic RNA (gRNA) in persistently infected cells. Furthermore, the CRISPR/Cas13 system targeting viral mRNAs also suppressed BoDV-1 infection if the system was introduced prior to the infection. Collectively, we demonstrated that the CRISPR/Cas13 system can suppress BoDV-1 in both acute and persistent infections. Our findings will open the avenue to treat prolonged infection with RNA viruses using the CRISPR/Cas13 system.
2023-04-10 | Impact of Borna Disease Virus Infection on the Transcriptome of Differentiated Neuronal Cells and Its Modulation by Antiviral Treatment
Borna disease virus (BoDV-1) is a highly neurotropic RNA virus that causes neurobehavioral disturbances such as abnormal social activities and memory impairment. Although impairments in the neural circuits caused by BoDV-1 infection induce these disturbances, the molecular basis remains unclear. Furthermore, it is unknown whether anti-BoDV-1 treatments can attenuate BoDV-1-mediated transcriptomic changes in neuronal cells. In this study, we investigated the effects of BoDV-1 infection on neuronal differentiation and the transcriptome of differentiated neuronal cells using persistently BoDV-1-infected cells. Although BoDV-1 infection did not have a detectable effect on intracellular neuronal differentiation processes, differentiated neuronal cells exhibited transcriptomic changes in differentiation-related genes. Some of these transcriptomic changes, such as the decrease in the expression of apoptosis-related genes, were recovered by anti-BoDV-1 treatment, while alterations in the expression of other genes remained after treatment. We further demonstrated that a decrease in cell viability induced by differentiation processes in BoDV-1-infected cells can be relieved with anti-BoDV-1 treatment. This study provides fundamental information regarding transcriptomic changes after BoDV-1 infection and the treatment in neuronal cells.
2022-02-14 | miR-505 inhibits replication of Borna disease virus 1 via inhibition of HMGB1-mediated autophagy.
Borna disease virus 1 (BoDV-1) is a highly neurotropic RNA virus which was recently demonstrated to cause deadly human encephalitis. Viruses can modulate microRNA expression, in turn modulating cellular immune responses and regulating viral replication. A previous study indicated that BoDV-1 infection down-regulated the expression of miR-505 in rats. However, the underlying mechanism of miR-505 during BoDV-1 infection remains unknown. In this study, we found that miR-505 can inhibit autophagy activation by down-regulating the expression of its target gene HMGB1, and ultimately inhibit the replication of BoDV-1. Specifically, we found that the expression of miR-505 was significantly down-regulated in rat primary neurons stably infected with BoDV-1. Overexpression of miR-505 can inhibit the replication of BoDV-1 in cells. Bioinformatics analysis and dual luciferase reporter gene detection confirmed that during BoDV-1 infection, the high-mobility group protein B1 (HMGB1) that mediates autophagy is the direct target gene of miR-505. The expression of HMGB1 was up-regulated after BoDV-1 infection, and overexpression of miR-505 could inhibit the expression of HMGB1. Autophagy-related detection found that after infection with BoDV-1, the expression of autophagy-related proteins and autophagy-related marker LC3 in neuronal cells was significantly up-regulated. Autophagy flow experiments and transmission electron microscopy also further confirmed that BoDV-1 infection activated HMGB1-mediated autophagy. Further regulating the expression of miR-505 found that overexpression of miR-505 significantly inhibited HMGB1-mediated autophagy. The discovery of this mechanism may provide new ideas and directions for the prevention and treatment of BoDV-1 infection in the future.
2019-07-19 | miR-146a promotes Borna disease virus 1 replication through IRAK1/TRAF6/NF-κB signaling pathway
: Borna disease virus 1 (BoDV-1) is a negative single-stranded RNA virus that is highly neurotropic. BoDV-1 infection can damage the central nervous system and cause inflammation. To survive in host cells, BoDV-1 must evade the host innate immune response. A previous study showed that miR-146a expression increased in neonatal rats infected with BoDV-1. miR-146a is a microRNA suggested to negatively regulate innate immune and inflammatory responses and antiviral pathways. Many groups have reported that its overexpression facilitates viral replication. However, it is unclear whether miR-146a is involved in escape from the host immune response during BoDV-1 infection. : In this study, BoDV-1 was used to infect neonatal rats within 24 h of birth intracranially, as well as to infect human microglial cells (HMC3). miR-146a expression was analyzed by RT-qPCR. The TargetScanHuman database was used to find the target genes of miR-146a. A search of the binding sites of miR-146a and its target gene's 3′-untranslated region (3′UTR) was also performed using RNAhybrid software. The binding sites of miR-146a and the target gene's 3′UTR were detected by dual luciferase reporter assays. Overexpression and suppression studies of miR-146a were performed to determine its effect on BoDV-1 replication. The relative protein expression of members of the IRAK1/TRAF6/NF-κB signaling pathway was also evaluated by western blotting in HMC3. : After BoDV-1 infection of neurons in vivo and of HMC3 cells, miR-146a expression was significantly upregulated. miR-146a overexpression in HMC3 cells promoted viral replication, while its inhibition inhibited it. Through the TargetScanHuman database, we identified the target genes of anti-inflammatory miR-146a: IRAK1 and TRAF6. We also found that BoDV-1 could inhibit IRAK1 and TRAF6 expression in HMC3 cells. Moreover, we showed that the inhibition of IRAK1 and TRAF6 also led to decreases in the expression of P65 and phosphorylated P65 in the downstream NF-κB pathway. Subsequently, we confirmed the interaction of miR-146a with IRAK1 and TRAF6 by luciferase assay. : Our results suggest that miR-146a inhibits the IRAK1/TRAF6/NF-κB signaling pathway to facilitate BoDV-1 survival in host cells.
small molecules
2026-05-29 | Structural mechanism of Borna disease virus 1 RNA polymerase autoinhibition and suramin-mediated inhibition.
Borna disease virus 1 (BoDV-1) is a neurotropic pathogen that causes severe, often fatal encephalitis, yet effective treatments remain unavailable. As a nuclear-replicating mononegavirus, BoDV-1 employs a minimal L-P polymerase complex. Here, we report cryo-electron microscopy (cryo-EM) structures of the BoDV-1 polymerase in L-alone, apo-L-P, and inhibitor-bound L-P states, revealing the most compact L protein characterized among mononegaviruses. While the catalytic core is conserved, the C-terminal domains are degenerate, with the methyltransferase-like (MTase-like) domain lacking canonical functional motifs. We identify an N-terminal autoinhibitory element (AIE) that is positioned to physically block the template entry tunnel, suggesting an autoinhibition mechanism reminiscent of a "molecular plug." Furthermore, we demonstrate that the inhibitor suramin binds in a specific triple-molecule mode, potentially achieving inhibition by sterically occluding RNA access and allosterically restricting the catalytic core. These findings elucidate the architecture and regulation of the BoDV-1 polymerase, providing a structural framework for rational antiviral design.
2026-05-14 | Multimodal profiling of immune responses reveals innate-adaptive immune imbalance in human bornavirus encephalitis
Abstract Human bornavirus encephalitis (BVE) is a rare, emerging and fatal zoonotic disease mainly caused by the Borna disease virus 1 (BoDV-1), a non-cytolytic RNA virus. Despite increasing recognition, the immunopathogenesis of human BoDV-1 infection remains insufficiently characterised. Complete coronal and sagittal brain sections from four fatal BoDV-1 cases were analysed using digitised immunohistochemistry to quantify viral distribution and tissue responses. Transcriptome-based analyses characterised local immune cell profiles in relation to viral loads measured by RT-qPCR. BoDV-1 viral loads varied substantially between cases but showed region-specific enrichment in the basal ganglia and hippocampus, correlating with lymphocyte presence and reactive microglia and astrocytes. Immune cell deconvolution revealed viral load-dependent modulation dominated by innate immune and glial populations, including metabolic and reactive astrocyte states, IFNγ-responsive microglia, and dendritic cells, macrophages, neutrophils, basophils, and CD8⁺ T cells. This was accompanied by induction of interferon-stimulated genes, antigen presentation, protein synthesis, and oxidative stress pathways, with a transcriptional signature resembling non-lytic viral and autoimmune-like neuroinflammatory conditions rather than lytic infections. These findings support a model of BoDV-1 encephalitis characterised by a prominent innate immune response and comparatively limited adaptive immune signatures. This imbalance might potentially contribute to impaired viral clearance and extensive tissue damage, a possible relationship that warrants further investigation.
2025-10-05 | First therapeutic drug monitoring of experimental favipiravir in Borna disease virus 1 (BoDV-1) encephalitis patients reveals significant gaps in antiviral treatment: a pilot investigation.
The Borna disease virus 1 (BoDV-1) causes a rare, but severe form of encephalitis in Germany, characterized by rapid progression, late diagnosis, and a high case fatality. Therapy is experimental and recommendations are lacking. Favipiravir (FPV) suppresses BoDV-1 replication in vitro and has been used in a handful of BoDV-1 patients within individual treatment attempts, but little is known about the drug´s pharmacokinetics in encephalitis. To monitor and therefore optimize experimental FPV treatment, we established a liquid chromatography tandem mass spectroscopy (LC-MS/MS) assay for serum and cerebrospinal fluid (CSF), and analyzed stored specimens of two patients with BoDV-1 encephalitis in the context of therapeutic drug monitoring as a pilot investigation. We demonstrate for the first time that orally administered FPV reaches the CSF in BoDV-1 encephalitis. However, the half-maximal inhibitory concentration (IC50) for BoDV-1 was met only in one patient, raising questions on significantly higher dosing and/or alternative formulations for effective treatment. In conclusion, monitoring experimental FPV therapy in BoDV-1 encephalitis is feasible and should be performed continuously. Future prospective in-depth (multicenter) studies should include more patients and focus on dose-finding, dose-response relationships, and define a therapeutic index to improve outcomes of this so far nearly uniformly fatal disease.
2025-09-25 | Structural insights into the dynamic mechanism of bornavirus polymerase.
Borna disease virus 1 (BoDV-1), an emerging zoonotic pathogen from the Bornaviridae family, is neurotropic and can infect a variety of mammalian hosts, including humans. Linked to severe encephalitis and high mortality, BoDV-1 currently lacks licensed treatments or vaccines. The BoDV-1 polymerase complex, comprising the large (L) and phosphoprotein (P) subunits, is crucial for viral replication and transcription, making it a promising target for antiviral intervention. Here, we present the cryoelectron microscopy structure of the apo BoDV-1 L-P complex, revealing a unique "mitten-shaped" architecture. The structure characterizes key domains involved in RNA synthesis, including RNA-dependent RNA polymerase, polyribonucleotidyltransferase, and an inactive methyltransferase domain. While no RNA or NTPs were visible, we observed distinct conformational states, showing large-scale rearrangements of the P tetramer and L domains, as well as remodeling of the RNA template, nucleoside triphosphates, and nascent RNA entrances and/or exits, upon introducing RNA and NTPs. These findings highlight the dynamic structural changes probably associated with polymerase activity and advance the understanding of the BoDV-1 polymerase mechanisms, offering a basis for developing targeted antiviral strategies against this deadly pathogen.
2025-08-04 | Demographic data on included humans and animals.
Borna disease virus 1 (BoDV-1) has long been recognized as a cause of fatal encephalitis in animals and was only recently identified as a zoonotic pathogen causing a similar disease in humans. This study provides the first comprehensive comparative analysis of BoDV-1-induced neuropathology in human and animal end hosts, including horses, sheep, and alpacas. Using immunohistochemical analyses, we investigated the topographical distribution of BoDV-1 and inflammatory responses in the central nervous system across 19 cases. Key findings reveal distinct differences and overlaps between humans and animals. While humans exhibited heterogeneous patterns especially of the lymphocyte infiltration, animals displayed more species-specific inflammation and viral spread patterns. In horses, the hippocampus and basal ganglia were consistently affected, whereas sheep showed predominant involvement of the frontal cortex and stria olfactoria. Alpacas demonstrated a less uniform distribution but highlighted the brainstem and basal ganglia as critical sites. Intriguingly, across all species, a negative association was observed between lymphocyte infiltration and the number of BoDV-1-infected cells. These findings enhance our understanding of BoDV-1 pathogenesis and is a first step of cross-species comparison in unraveling disease mechanisms in BoDV-1 infection. Further research is warranted to elucidate the implications of these findings for therapeutic strategies and to explore the entry and dissemination routes of BoDV-1 in different hosts.
antibodies
2026-08-13 | Long-Term Survival of Borna Disease Virus 1 (BoDV-1)-Encephalitis: An Exceptional Case with Valuable Insights for Pathophysiology and Disease Management.
Borna disease virus 1 (BoDV-1) encephalitis has a (sub)acute and mostly fatal course. Initial flu-like symptoms are typically followed by rapid progressive panencephalitis and death within weeks. No curative therapy exists so far. We present a long-term survivor with distinctive clinical, imaging, and pathophysiological features. A previously healthy male in his fifties was admitted in summer 2023 with (sub)acute encephalitis (cerebrospinal fluid, CSF: 132 cells/µl, no pathogen detection). Brain magnetic resonance imaging (MRI) demonstrated vasogenic edema affecting basal ganglia, temporal and limbic regions bilaterally. Despite high-dose steroids, the clinical condition of the patient slowly worsened. Three months later, BoDV-1 reactive antibodies were detected by elevated titers in CSF (1:320) and serum (1:5120). Treatment with favipiravir, corticosteroids, and mycophenolate mofetil (MMF) was initiated. After recovery for months, the patient developed progressive bilateral optic atrophy, cognitive decline, and a sleep disorder resembling Kleine-Levin syndrome. Translocator protein (TSPO)-PET revealed widespread microglial activation, confirmed by targeted cortical biopsy. Immunosuppressive therapy was escalated with anakinra, cyclophosphamide, and intrathecal dexamethasone, achieving temporary stabilization. In the summer of 2025, a severe brainstem syndrome emerged, accompanied by increased TSPO uptake in the brainstem and detection of BoDV-1 RNA in CSF for the first time. Despite another treatment with favipiravir and high-dose corticosteroids, the patient remained in a minimally conscious state. This exceptional case with long-term survival in BoDV-1 encephalitis gives important insights: BoDV1-associated neuroinflammation leading to a slowly progressive decline can be visualized by TSPO-PET. Late BoDV-1 RNA detection and subacute re-exacerbation after prolonged survival provides evidence that BoDV-1 persists in human brain tissue.
2001-01-15 | Neutralizing Antibodies in Persistent Borna Disease Virus Infection: Prophylactic Effect of gp94-Specific Monoclonal Antibodies in Preventing Encephalitis
Borna disease virus (BDV) infection triggers an immune-mediated encephalomyelitis and results in a persistent infection. The immune response in the acute phase of the disease is characterized by a cellular response in which CD8(+) T cells are responsible for the destruction of virus-infected brain cells. CD4(+) T cells function as helper cells and support the production of antiviral antibodies. Antibodies generated in the acute phase of the disease against the nucleoprotein and the phosphoprotein are nonneutralizing. In the chronic phase of the disease, neutralizing antibodies directed against the matrix protein and glycoprotein are synthesized. In the present work, the biological role of the neutralizing-antibody response to BDV was further investigated. By analyzing the blood of rats infected intracerebrally with BDV, a highly neurotropic virus, nucleic acid could be detected between 30 and 50 days after infection. Neutralizing antibodies were found between 60 and 100 days after infection. Furthermore, we produced hybridomas secreting BDV-specific neutralizing monoclonal antibodies. These antibodies, directed against the major glycoprotein (gp94) of BDV, were able to prevent Borna disease if given prophylactically. These data suggest that the late appearance of BDV-specific neutralizing antibodies is due to the presence of BDV in the blood of chronically infected rats. Furthermore, these antibodies have the potential to neutralize the infectious virus when given early, which is an important finding with respect to the development of a vaccine.
1998-06-25 | In vivo treatment with anti-alpha4 integrin suppresses clinical and pathological evidence of Borna disease virus infection.
Borna disease virus (BDV) infection of the rat brain induces a severe T-lymphocyte mediated inflammatory response that parallels the course of clinical Borna disease. In other models of CNS inflammation, the recruitment of T-lymphocytes from the circulation to sites of inflammation is believed to be directed, in part, by the cellular adhesion molecules alpha4 beta1 integrin (expressed on T-lymphocytes) and its ligand VCAM-1 (expressed on blood brain barrier endothelium). Since BDV-specific T-lymphocytes are known to express the alpha4 beta1 integrin, we examined the effect of in vivo treatment with an anti-alpha4 integrin monoclonal antibody (GG5/3) on the development of BDV-specific encephalitis and Borna disease. Here, we report that the inhibition of alpha4 integrin provided significant clinical benefit in slowing the progression of Borna disease. Antibody treatment greatly reduced the immune cell infiltrates in the CNS of BDV-infected animals, but we found that this inhibition of the immune response did not result in enhanced viral levels.
1993-12-09 | Brain cell lesions in Borna disease are mediated by T cells.
Experimental Borna Disease (BD) in rats is characterized by severe lymphocytic encephalitis and by massive brain cell lesions finally leading to brain atrophy. Treatment of BDV-infected rats with monoclonal antibodies directed against CD4+ and CD8+ T cells could almost completely inhibit the immunopathological reactions and revealed less BDV-infected neurons and astrocytes that expressed MHC class I antigen. Brain cell lesions were minimal, and no obvious brain atrophy could be observed even late after infection. Since BDV itself is not known to exert cytopathic effects and since brain cell damage was independent of antibody titers, brain cell destruction correlates well with the intracerebral presence of CD8+ T cells and the expression of MHC class I antigens. Moreover, BDV-infected brain cells in vitro could be demonstrated to be lysed in a MHC class I-restricted manner. These findings provide evidence that virus-infected neurons can be destructed by T cell mediated cytotoxicity which results in organ atrophy and dementia.
1992-06-16 | Preventive effects of early anti-CD4 or anti-CD8 treatment on Borna disease in rats.
Borna disease is a virus-induced, immunopathological encephalomyelitis in which CD4+ cells and macrophages dominate the pathological picture. However, significant numbers of CD8+ cells have been morphologically identified in perivascular infiltrates as well. To determine the contribution of different T-cell subsets to the pathogenesis of Borna disease, virus-infected rats were treated with monoclonal antibodies specific for CD4+ and CD8+ cells. Both types of monoclonal antibodies were able to significantly decrease or even prevent the local inflammatory reaction in the brain if given early during the infection. However, CD8-specific monoclonal antibodies appeared to be more effective than antibodies directed against CD4+ cells. Treatment initiated 4 days postinfection did not result in inhibition of encephalitis and disease. Virus titers in the brain of infected rats treated with T-cell-specific antibodies did not differ from titers in untreated infected control animals. The results indicate an important functional role of CD8+ cells, in addition to CD4+ cells, in the pathogenesis of Borna disease.
vaccines
2025-10-13 | Is vaccination a feasible public health strategy against fatal Borna disease virus 1 (BoDV-1) encephalitis? An epidemiological perspective.
Human Borna disease virus 1 (BoDV-1) encephalitis is characterized by rapid clinical progression, an absence of a causal therapy and an extremely high case fatality rate. Here, we discuss prevention options through a hypothetical vaccine focusing on epidemiological features.
2024-12-20 | Developing a universal multi-epitope protein vaccine candidate for enhanced borna virus pandemic preparedness.
Borna disease virus 1 (BoDV-1) is an emerging zoonotic RNA virus that can cause severe acute encephalitis with high mortality. Currently, there are no effective countermeasures, and the potential risk of a future outbreak requires urgent attention. To address this challenge, the complete genome sequence of BoDV-1 was utilized, and immunoinformatics was applied to identify antigenic peptides suitable for vaccine development. Immunoinformatics and antigenicity-focused protein screening were employed to predict B-cell linear epitopes, B-cell conformational epitopes, and cytotoxic T lymphocyte (CTL) epitopes. Only overlapping epitopes with antigenicity greater than 1 and non-toxic, non-allergenic properties were selected for subsequent vaccine construction. The epitopes were linked using GPGPG linkers, incorporating β-defensins at the N-terminus to enhance immune response, and incorporating Hit-6 at the C-terminus to improve protein solubility and aid in protein purification. Computational tools were used to predict the immunogenicity, physicochemical properties, and structural stability of the vaccine. Molecular docking was performed to predict the stability and dynamics of the vaccine in complex with Toll-like receptor 4 (TLR-4) and major histocompatibility complex I (MHC I) receptors. The vaccine construct was cloned through in silico restriction to create a plasmid for expression in a suitable host. Among the six BoDV-1 proteins analyzed, five exhibited high antigenicity scores. From these, eight non-toxic, non-allergenic overlapping epitopes with antigenicity scores greater than 1 were selected for vaccine development. Computational predictions indicated favorable immunogenicity, physicochemical properties, and structural stability. Molecular docking analysis showed that the vaccine remained stable in complex with TLR-4 and MHC I receptors, suggesting strong potential for immune recognition. A plasmid construct was successfully generated, providing a foundation for the experimental validation of vaccines in future pandemic scenarios. These findings demonstrate the potential of the immunoinformatics-designed multi-epitope vaccines for the prevention and treatment of BoDV-1. Relevant preparations were made in advance for possible future outbreaks and could be quickly utilized for experimental verification.
2022-12-26 | Vaccination against Borna Disease: Overview, Vaccine Virus Characterization and Investigation of Live and Inactivated Vaccines.
(1) Background: Vaccination of horses and sheep against Borna disease (BD) was common in endemic areas of Germany in the 20th century but was abandoned in the early 1990s. The recent occurrence of fatal cases of human encephalitis due to Borna disease virus 1 (BoDV-1) has rekindled the interest in vaccination. (2) Methods: The full genomes of the BD live vaccine viruses "Dessau" and "Giessen" were sequenced and analyzed for the first time. All vaccination experiments followed a proof-of-concept approach. Dose-titration infection experiments were performed in rabbits, based on both cell culture- and brain-derived viruses at various doses. Inactivated vaccines against BD were produced from concentrated cell culture supernatants and investigated in rabbits and horses. The BoDV-1 live vaccine "Dessau" was administered to horses and antibody profiles were determined. (3) Results: The BD live vaccine viruses "Dessau" and "Giessen" belong to clusters 3 and 4 of BoDV-1. Whereas the "Giessen" virus does not differ substantially from field viruses, the "Dessau" virus shows striking differences in the M gene and the N-terminal part of the G gene. Rabbits infected with high doses of cell-cultured virus developed neutralizing antibodies and were protected from disease, whereas rabbits infected with low doses of cell-cultured virus, or with brain-derived virus did not. Inactivated vaccines were administered to rabbits and horses, following pre-defined vaccination schemes consisting of three vaccine doses of either adjuvanted or nonadjuvanted inactivated virus. Their immunogenicity and protective efficacy were compared to the BD live vaccine "Dessau". Seventy per cent of horses vaccinated with the BD live vaccine "Dessau" developed neutralizing antibodies after vaccination. (4) Conclusion: Despite a complex evasion of immunological responses by bornaviruses, some vaccination approaches can protect against clinical disease. For optimal effectiveness, vaccines should be administered at high doses, following vaccination schemes consisting of three vaccine doses as basic immunization. Further investigations are necessary in order to investigate and improve protection against infection and to avoid side effects.
2005-01-19 | Vaccine-induced protection against Borna disease in wild-type and perforin-deficient mice
Borna disease virus (BDV) can persistently infect the central nervous system and induce CD8 + T-cell-mediated neurological disease in MRL mice. To determine whether specific immune priming would prevent disease, a prime–boost immunization protocol was established in which intramuscular injection of a recombinant parapoxvirus expressing BDV nucleoprotein (BDV-N) was followed by intraperitoneal infection with vaccinia virus expressing BDV-N. Immunized wild-type and perforin-deficient mice remained healthy after intracerebral infection with BDV and contained almost no virus in the brain at 5 weeks post-challenge. Immunization failed to induce resistance against BDV in mice lacking mature CD8 + T cells. Immunization of perforin-deficient mice with a poxvirus vector expressing mutant BDV-N lacking the known CD8 + T-cell epitope did not efficiently block multiplication of BDV in the brain and did not prevent neurological disease, indicating that vaccine-induced immunity to BDV in wild-type and perforin-deficient mice resulted from the action of CD8 + T cells.
2001-12-01 | High-Dose Borna Disease Virus Infection Induces a Nucleoprotein-Specific Cytotoxic T-Lymphocyte Response and Prevention of Immunopathology
ABSTRACT Experimental Borna disease virus (BDV) infection of rats and natural infection of horses and sheep leads to severe central nervous system disease based on immunopathological pathways. The virus replicates slowly, and the cellular immune response results in immunopathology. CD8 + T cells exert effector cell functions, and their activity results in the destruction of virus-infected cells. Previously, Oldach and colleagues (D. Oldach, M. C. Zink, J. M. Pyper, S. Herzog, R. Rott, O. Narayan, and J. E. Clements, Virology 206:426–434, 1995) have reported protection against Borna disease after inoculation of high-dose cell-adapted BDV. Here we show that the outcome of the infection, i.e., immunopathology versus protection, is simply dependent on the amount of virus used for infection. High-dose BDV (10 6 FFU) triggers an early virus-specific reaction of the immune system, as demonstrated by strong cellular and humoral responses. In particular, the early presence and function of nucleoprotein-specific CD8 + T cells could be demonstrated in the brain. We present evidence that in a noncytolytic and usually persistent virus infection, high-dose input virus mediates early control of the pathogen due to an efficient induction of an antiviral immune mechanism. From these data, we conclude that immune reactivity, in particular the cytotoxic T-cell response, determines whether the virus is controlled with prevention of the ensuing immunopathological disease or whether a persistent infection is established.
gene therapies
2024-04-15 | The absence of superinfection exclusion of Borna disease virus 2 maintains genomic polymorphisms in persistently infected cells
Abstract Viruses belonging to the genus Orthobornavirus within the family Bornaviridae are known to infect various vertebrate species, including mammals and birds. Within the genus, the species Orthobornavirus bornaense includes two mammalian viruses: Borna disease virus 1 (BoDV-1), the prototype of the family, and its closely related virus, BoDV-2. BoDV-1 was identified as the causative agent of Borna disease (BD) in horses, sheep, humans, and other mammals. BoDV-2 was first detected in a pony in eastern Austria in 1999 that exhibited severe and incurable neurological symptoms. Although BoDV-2 shares approximately 80% nucleotide identity with BoDV-1, its virological properties, including host range, replication ability, and pathogenicity, remain unclear. In this study, we aimed to investigate the virological properties of BoDV-2 by re-evaluating its whole-genome sequence using RNA sequencing. Compared to the published reference sequence, we identified two nonsynonymous nucleotide substitutions in the large (L) gene. One of these substitutions was found to be critical for the restoration of polymerase activity, enabling the successful recovery of recombinant BoDV-2 (rBoDV-2) through reverse genetics. We also identified two nonsynonymous single-nucleotide polymorphisms (SNPs) in the L gene and one in the phosphoprotein (P) gene. Substitution of these SNPs significantly enhanced the growth ability of rBoDV-2. In addition, our studies showed that BoDV-2 does not induce superinfection exclusion in cells, allowing persistence of low-fitness genome variants for an extended period of time. These findings help to characterize the virological properties of BoDV-2 and shed light on how bornaviruses maintain genetic diversity in infected cells. Importance Mammalian bornaviruses are a general term for viruses belonging to the genus Orthobornavirus that infect mammalian species, e.g., Borna disease virus 1 and 2 (BoDV-1 and -2) and variegated squirrel bornavirus 1 (VSBV-1). Although BoDV-1 and VSBV-1 are reported to be associated with fatal encephalitis in humans, the infectivity and pathogenicity of BoDV-2 in humans remain unclear. To determine the virological properties of BoDV-2, we developed a reverse genetics system for BoDV-2. By using recombinant BoDV-2s, we identified several nucleotides that affect the growth ability of BoDV-2 and revealed the molecular mechanisms through which BoDV-2 maintains genetic heterogeneity in persistently infected cells. This reverse genetics system will accelerate the biological studies of BoDV-2 and contribute to the development of countermeasures against mammalian bornaviruses.
2024-03-20 | Suppression of Borna Disease Virus Replication during Its Persistent Infection Using the CRISPR/Cas13b System
Borna disease virus (BoDV-1) is a bornavirus that infects the central nervous systems of various animal species, including humans, and causes fatal encephalitis. BoDV-1 also establishes persistent infection in neuronal cells and causes neurobehavioral abnormalities. Once neuronal cells or normal neural networks are lost by BoDV-1 infection, it is difficult to regenerate damaged neural networks. Therefore, the development of efficient anti-BoDV-1 treatments is important to improve the outcomes of the infection. Recently, one of the clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) systems, CRISPR/Cas13, has been utilized as antiviral tools. However, it is still unrevealed whether the CRISPR/Cas13 system can suppress RNA viruses in persistently infected cells. In this study, we addressed this question using persistently BoDV-1-infected cells. The CRISPR/Cas13 system targeting viral mRNAs efficiently decreased the levels of target viral mRNAs and genomic RNA (gRNA) in persistently infected cells. Furthermore, the CRISPR/Cas13 system targeting viral mRNAs also suppressed BoDV-1 infection if the system was introduced prior to the infection. Collectively, we demonstrated that the CRISPR/Cas13 system can suppress BoDV-1 in both acute and persistent infections. Our findings will open the avenue to treat prolonged infection with RNA viruses using the CRISPR/Cas13 system.
2023-04-10 | Impact of Borna Disease Virus Infection on the Transcriptome of Differentiated Neuronal Cells and Its Modulation by Antiviral Treatment
Borna disease virus (BoDV-1) is a highly neurotropic RNA virus that causes neurobehavioral disturbances such as abnormal social activities and memory impairment. Although impairments in the neural circuits caused by BoDV-1 infection induce these disturbances, the molecular basis remains unclear. Furthermore, it is unknown whether anti-BoDV-1 treatments can attenuate BoDV-1-mediated transcriptomic changes in neuronal cells. In this study, we investigated the effects of BoDV-1 infection on neuronal differentiation and the transcriptome of differentiated neuronal cells using persistently BoDV-1-infected cells. Although BoDV-1 infection did not have a detectable effect on intracellular neuronal differentiation processes, differentiated neuronal cells exhibited transcriptomic changes in differentiation-related genes. Some of these transcriptomic changes, such as the decrease in the expression of apoptosis-related genes, were recovered by anti-BoDV-1 treatment, while alterations in the expression of other genes remained after treatment. We further demonstrated that a decrease in cell viability induced by differentiation processes in BoDV-1-infected cells can be relieved with anti-BoDV-1 treatment. This study provides fundamental information regarding transcriptomic changes after BoDV-1 infection and the treatment in neuronal cells.
2022-02-14 | miR-505 inhibits replication of Borna disease virus 1 via inhibition of HMGB1-mediated autophagy.
Borna disease virus 1 (BoDV-1) is a highly neurotropic RNA virus which was recently demonstrated to cause deadly human encephalitis. Viruses can modulate microRNA expression, in turn modulating cellular immune responses and regulating viral replication. A previous study indicated that BoDV-1 infection down-regulated the expression of miR-505 in rats. However, the underlying mechanism of miR-505 during BoDV-1 infection remains unknown. In this study, we found that miR-505 can inhibit autophagy activation by down-regulating the expression of its target gene HMGB1, and ultimately inhibit the replication of BoDV-1. Specifically, we found that the expression of miR-505 was significantly down-regulated in rat primary neurons stably infected with BoDV-1. Overexpression of miR-505 can inhibit the replication of BoDV-1 in cells. Bioinformatics analysis and dual luciferase reporter gene detection confirmed that during BoDV-1 infection, the high-mobility group protein B1 (HMGB1) that mediates autophagy is the direct target gene of miR-505. The expression of HMGB1 was up-regulated after BoDV-1 infection, and overexpression of miR-505 could inhibit the expression of HMGB1. Autophagy-related detection found that after infection with BoDV-1, the expression of autophagy-related proteins and autophagy-related marker LC3 in neuronal cells was significantly up-regulated. Autophagy flow experiments and transmission electron microscopy also further confirmed that BoDV-1 infection activated HMGB1-mediated autophagy. Further regulating the expression of miR-505 found that overexpression of miR-505 significantly inhibited HMGB1-mediated autophagy. The discovery of this mechanism may provide new ideas and directions for the prevention and treatment of BoDV-1 infection in the future.
2019-07-19 | miR-146a promotes Borna disease virus 1 replication through IRAK1/TRAF6/NF-κB signaling pathway
: Borna disease virus 1 (BoDV-1) is a negative single-stranded RNA virus that is highly neurotropic. BoDV-1 infection can damage the central nervous system and cause inflammation. To survive in host cells, BoDV-1 must evade the host innate immune response. A previous study showed that miR-146a expression increased in neonatal rats infected with BoDV-1. miR-146a is a microRNA suggested to negatively regulate innate immune and inflammatory responses and antiviral pathways. Many groups have reported that its overexpression facilitates viral replication. However, it is unclear whether miR-146a is involved in escape from the host immune response during BoDV-1 infection. : In this study, BoDV-1 was used to infect neonatal rats within 24 h of birth intracranially, as well as to infect human microglial cells (HMC3). miR-146a expression was analyzed by RT-qPCR. The TargetScanHuman database was used to find the target genes of miR-146a. A search of the binding sites of miR-146a and its target gene's 3′-untranslated region (3′UTR) was also performed using RNAhybrid software. The binding sites of miR-146a and the target gene's 3′UTR were detected by dual luciferase reporter assays. Overexpression and suppression studies of miR-146a were performed to determine its effect on BoDV-1 replication. The relative protein expression of members of the IRAK1/TRAF6/NF-κB signaling pathway was also evaluated by western blotting in HMC3. : After BoDV-1 infection of neurons in vivo and of HMC3 cells, miR-146a expression was significantly upregulated. miR-146a overexpression in HMC3 cells promoted viral replication, while its inhibition inhibited it. Through the TargetScanHuman database, we identified the target genes of anti-inflammatory miR-146a: IRAK1 and TRAF6. We also found that BoDV-1 could inhibit IRAK1 and TRAF6 expression in HMC3 cells. Moreover, we showed that the inhibition of IRAK1 and TRAF6 also led to decreases in the expression of P65 and phosphorylated P65 in the downstream NF-κB pathway. Subsequently, we confirmed the interaction of miR-146a with IRAK1 and TRAF6 by luciferase assay. : Our results suggest that miR-146a inhibits the IRAK1/TRAF6/NF-κB signaling pathway to facilitate BoDV-1 survival in host cells.
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