Search Results (14)

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. Full article

Borna disease virus 1 (BoDV1) causes a persistent infection in the mammalian brain. Peroxisomes and mitochondria play essential roles in the cellular antiviral immune response, but the effect of BoDV1 infection on peroxisomal and mitochondrial dynamics and their respective antioxidant capacities is still not clear. Using different mouse lines—i.e., tumor necrosis factor-α transgenic (TNFTg; to pro-inflammatory status), TNF receptor-1 knockout (TNFR1ko), and TNFR2ko mice in comparison to wild-type (Wt) mice—we analyzed the abundances of both organelles and their main antioxidant enzymes, catalase and superoxide dismutase 2 (SOD2), in neurons of the hippocampal, cerebral, and cerebellar cortices. In TNFTg mice, a strong increase in mitochondrial (6.9-fold) and SOD2 (12.1-fold) abundances was detected; meanwhile, peroxisomal abundance increased slightly (1.5-fold), but that of catalase decreased (2.9-fold). After BoDV1 infection, a strong decrease in mitochondrial (2.1–6.5-fold), SOD2 (2.7–9.1-fold), and catalase (2.7–10.3-fold) abundances, but a slight increase in peroxisomes (1.3–1.6-fold), were detected in Wt and TNFR2ko mice, whereas no changes occurred in TNFR1ko mice. Our data suggest that the TNF system plays a crucial role in the biogenesis of both subcellular organelles. Moreover, TNFR1 signaling mediated the changes in peroxisomal and mitochondrial dynamics after BoDV1 infection, highlighting new mechanisms by which BoDV1 may achieve immune evasion and viral persistence. Full article

Human cases of fatal encephalitis caused by Borna disease virus 1 (BoDV-1) have been increasingly reported. We envisaged the present systematic review in order to provide a comprehensive summary of clinical features associated with BoDV-1 encephalitis. Systematic research of four databases (PubMed, EMBASE, MedRxiv, BioRxiv) was performed during July 2023, and corresponding clinical and epidemiological data were collected and analyzed. A total of 37 BoDV-1 encephalitis cases from 15 different study cases and two countries (Germany, No. 35; France, No. 2) were detected, and their features were summarized (case fatality ratio, 91.9%). Age distribution followed a “U-shaped” distribution, with a first peak in individuals younger than 14 years (18.9%) and the second one in subjects older than 50 years (43.2%). Environmental risk factors were irregularly reported, but 17 out of 37 cases either lived in rural areas or reported repeated outdoor activities (45.9%). Interaction with pets and livestock was reported in eight cases (21.6%), stressing the zoonotic potential of BoDV-1 infections. Moreover, 16.2% of cases were reported among recipients of solid organ transplantations (five kidneys; one liver). Overall survival in children/adolescents vs. adults (≥18 years) was not significantly different (Hazard Ratio 0.878; 95% Confidence Interval from 0.366 to 2.105). Magnetic Resonance Imaging identified the involvement of basal ganglia, mostly of the caudate nucleus (42.4%) and thalamus (33.3%). Cerebrospinal fluid was often characterized by pleocytosis (78.4%). On the other hand, no distinctive clinical features were identified: initial symptoms were specific and included headache, fever, and confusion. In conclusion, BoDV-1 infection can result in fatal encephalitis, whose actual burden still remains unascertained. As the epidemiology of BoDV-1 is similarly elusive, encephalitis cases of unclear cause should be routinely tested for bornaviruses. Full article

Borna disease virus 1 (BoDV-1) can cause a severe human syndrome characterized by meningo-myeloencephalitis. The actual epidemiology of BoDV-1 remains disputed, and our study summarized prevalence data among children and adolescents (<18-year-old). Through systematic research on three databases (PubMed, EMBASE, MedRxiv), all studies, including seroprevalence rates for BoDV-1 antigens and specific antibodies, were retrieved, and their results were summarized. We identified a total of six studies for a total of 2692 subjects aged less than 18 years (351 subjects sampled for BoDV-1 antibodies and 2557 for antigens). A pooled seroprevalence of 6.09% (95% Confidence Interval [95% CI] 2.14 to 16.17) was eventually calculated for BoDV-1 targeting antibodies and 0.76% (95% CI 0.26 to 2.19) for BoDV-1 antigens. Both estimates were affected by substantial heterogeneity. Seroprevalence rates for BoDV-1 in children and adolescents suggested that a substantial circulation of the pathogen does occur, and as infants and adolescents have relatively scarce opportunities for being exposed to hosts and animal reservoirs, the potential role of unknown vectors cannot be ruled out. Full article

Clinical cases of ‘staggering disease’, a nonsuppurative encephalomyelitis associated with gait abnormalities in cats, have been documented for decades in Sweden. In Austria, an increased incidence was observed in the 1990s. Only recently, rustrela virus (RusV) was identified as the causative agent of this clinicopathologic disease entity. In this retrospective study, we analyzed a total of 23 brain and spinal cord samples from Austrian cats with the pathohistological diagnosis of nonsuppurative encephalomyelitis and clinical signs consistent with staggering disease from 1994 to 2016 using reverse transcription real-time polymerase chain reaction (RT-qPCR) and in situ hybridization. We were able to detect RusV nucleic acids in seven of the examined samples. Borna disease virus 1 (BoDV-1) could be excluded in all cases via immunohistochemistry and RT-qPCR. This study confirms that RusV has been a relevant etiological agent of nonsuppurative encephalomyelitis of cats in a geographically and temporally limited disease cluster in Austria, mainly in the 1990s. The geographic distribution of the positive samples in this study is consistent with earlier reports on ‘staggering disease’ in Austria. Further studies are necessary to confirm the reservoir host of ‘staggering disease’ in Austria, as well as investigations on the disappearance of this disease and its possible zoonotic potential. Full article

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. Full article

More than 40 human infections with the zoonotic Borna disease virus 1 (BoDV-1) have been reported to German health authorities from endemic regions in southern and eastern Germany. Diagnosis of a confirmed case is based on the detection of BoDV-1 RNA or BoDV-1 antigen. In parallel, serological assays such as ELISA, immunoblots, and indirect immunofluorescence are in use to detect the seroconversion of Borna virus-reactive IgG in serum or cerebrospinal fluid (CSF). As immunopathogenesis in BoDV-1 encephalitis appears to be driven by T cells, we addressed the question of whether an IFN-γ-based ELISpot may further corroborate the diagnosis. For three of seven BoDV-1-infected patients, peripheral blood mononuclear cells (PBMC) with sufficient quantity and viability were retrieved. For all three patients, counts in the range from 12 to 20 spot forming units (SFU) per 250,000 cells were detected upon the stimulation of PBMC with a peptide pool covering the nucleocapsid protein of BoDV-1. Additionally, individual patients had elevated SFU upon stimulation with a peptide pool covering X or phosphoprotein. Healthy blood donors (n = 30) and transplant recipients (n = 27) were used as a control and validation cohort, respectively. In this pilot study, the BoDV-1 ELISpot detected cellular immune responses in human patients with BoDV-1 infection. Its role as a helpful diagnostic tool needs further investigation in patients with BoDV-1 encephalitis. Full article

More than 40 human cases of severe encephalitis caused by Borna disease virus 1 (BoDV-1) have been reported to German health authorities. In an endemic region in southern Germany, we conducted the seroepidemiological BoSOT study (“BoDV-1 after solid-organ transplantation”) to assess whether there are undetected oligo- or asymptomatic courses of infection. A total of 216 healthy blood donors and 280 outpatients after solid organ transplantation were screened by a recombinant BoDV-1 ELISA followed by an indirect immunofluorescence assay (iIFA) as confirmatory test. For comparison, 288 serum and 258 cerebrospinal fluid (CSF) samples with a request for tick-borne encephalitis (TBE) diagnostics were analyzed for BoDV-1 infections. ELISA screening reactivity rates ranged from 3.5% to 18.6% depending on the cohort and the used ELISA antigen, but only one sample of a patient from the cohort with requested TBE diagnostics was confirmed to be positive for anti-BoDV-1-IgG by iIFA. In addition, the corresponding CSF sample of this patient with a three-week history of severe neurological disease tested positive for BoDV-1 RNA. Due to the iIFA results, all other results were interpreted as false-reactive in the ELISA screening. By linear serological epitope mapping, cross-reactions with human and bacterial proteins were identified as possible underlying mechanism for the false-reactive ELISA screening results. In conclusion, no oligo- or asymptomatic infections were detected in the studied cohorts. Serological tests based on a single recombinant BoDV-1 antigen should be interpreted with caution, and an iIFA should always be performed in addition. Full article

(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. Full article

Determining the structural organisation of viral replication complexes and unravelling the impact of infection on cellular homeostasis represent important challenges in virology. This may prove particularly useful when confronted with viruses that pose a significant threat to human health, that appear unique within their family, or for which knowledge is scarce. Among Mononegavirales, bornaviruses (family Bornaviridae) stand out due to their compact genomes and their nuclear localisation for replication. The recent recognition of the zoonotic potential of several orthobornaviruses has sparked a surge of interest in improving our knowledge on this viral family. In this work, we provide a complete analysis of the structural organisation of Borna disease virus 1 (BoDV-1) phosphoprotein (P), an important cofactor for polymerase activity. Using X-ray diffusion and diffraction experiments, we revealed that BoDV-1 P adopts a long coiled-coil α-helical structure split into two parts by an original β-strand twist motif, which is highly conserved across the members of whole Orthobornavirus genus and may regulate viral replication. In parallel, we used BioID to determine the proximal interactome of P in living cells. We confirmed previously known interactors and identified novel proteins linked to several biological processes such as DNA repair or mRNA metabolism. Altogether, our study provides important structure/function cues, which may improve our understanding of BoDV-1 pathogenesis. Full article

Borna disease virus 1 (BoDV-1) is a neurotropic RNA virus belonging to the family Bornaviridae within the order Mononegavirales. Whereas BoDV-1 causes neurological and behavioral disorders, called Borna disease (BD), in a wide range of mammals, its virulence in humans has been debated for several decades. However, a series of case reports in recent years have established the nature of BoDV-1 as a zoonotic pathogen that causes fatal encephalitis in humans. Although many virological properties of BoDV-1 have been revealed to date, the mechanism by which it causes fatal encephalitis in humans remains unclear. In addition, there are no effective vaccines or antiviral drugs that can be used in clinical practice. A reverse genetics approach to generating replication-competent recombinant viruses from full-length cDNA clones is a powerful tool that can be used to not only understand viral properties but also to develop vaccines and antiviral drugs. The rescue of recombinant BoDV-1 (rBoDV-1) was first reported in 2005. However, due to the slow nature of the replication of this virus, the rescue of high-titer rBoDV-1 required several months, limiting the use of this system. This review summarizes the history of the reverse genetics and artificial replication systems for orthobornaviruses and explores the recent progress in efforts to rescue rBoDV-1. Full article

Amantadine (1-amino-adamantane) is a versatile antiviral compound which has been licensed for decades against influenza viruses. During the Corona pandemic, its effect to inhibit SARS-CoV-2 in vitro has been investigated. However, an in vivo oral inapplicability was concluded due to ID₅₀ doses exceeding eight times the estimated maximum tolerable plasma levels reached by 600 mg orally daily. In contrast, amantadine has been shown to be extraordinarily efficient against human neurotropic Borna disease virus (BoDV-1), presenting with both anti-depressive and anti-viral efficacy against a placebo, achieved by a well-tolerated low oral daily dose of 200 mg amantadine. Full article

A final diagnosis in a horse with clinical signs of encephalopathy can be challenging despite the use of extensive diagnostics. Clinical signs are often not pathognomonic and need to be interpreted in combination with (specific) laboratory results and epidemiological data of the geographical region of the origin of the case(s). Here we describe the diagnostic pathway of tick-borne encephalitis virus infection in two horses using established molecular diagnostic methods and a novel in situ hybridization technique to differentiate between regionally important/emerging diseases for central Europe: (i) hepatoencephalopathy, (ii) Borna disease virus, and (iii) West Nile virus infections. Full article

Mammalian Bornavirus (BoDV-1) typically causes a fatal neurologic disorder in horses and sheep, and was recently shown to cause fatal encephalitis in humans with and without transplant reception. It has been suggested that BoDV-1 enters the central nervous system (CNS) via the olfactory pathway. However, (I) susceptible cell types that replicate the virus for successful spread, and (II) the role of olfactory ensheathing cells (OECs), remained unclear. To address this, we studied the intranasal infection of adult rats with BoDV-1 in vivo and in vitro, using olfactory mucosal (OM) cell cultures and the cultures of purified OECs. Strikingly, in vitro and in vivo, viral antigen and mRNA were present from four days post infection (dpi) onwards in the olfactory receptor neurons (ORNs), but also in all other cell types of the OM, and constantly in the OECs. In contrast, in vivo, BoDV-1 genomic RNA was only detectable in adult and juvenile ORNs, nerve fibers, and in OECs from 7 dpi on. In vitro, the rate of infection of OECs was significantly higher than that of the OM cells, pointing to a crucial role of OECs for infection via the olfactory pathway. Thus, this study provides important insights into the transmission of neurotropic viral infections with a zoonotic potential. Full article