Borna disease virus 1 (BoDV-1) is a zoonotic member of the family Bornaviridae that is harbored by the bicolored white-toothed shrew (Crocidura leucodon) and can cause rare but severe human encephalitis in Central Europe[1–3]. Virologically, BoDV-1 is an enveloped, non-segmented, negative-sense RNA virus within the order Mononegavirales, with an approximately 8.9 kb genome whose replication and transcription occur in the host cell nucleus[4, 5]. Since molecular confirmation of human infection in 2018, increasing numbers of sporadic and transplant-associated cases have been recognized in Germany, with surveillance strengthened by mandatory reporting of direct pathogen detection introduced in 2020[6–8]. Epidemiologic syntheses indicate that BoDV-1 disease is concentrated in endemic regions of Germany and neighboring countries (e.g., Austria, Switzerland, Liechtenstein), and that transmission routes to humans remain uncertain, likely involving peridomestic exposure in rural settings, with solid organ transplantation representing the only clearly documented human-to-human route[4, 8, 9]. Clinically, illness often begins with non-specific flu-like symptoms (e.g., fever and headache) and progresses rapidly to severe encephalopathy, deep coma, and death in most patients, yielding case-fatality rates generally exceeding 90% across published series[5, 10, 11]. Diagnosis is challenging because cerebrospinal fluid (CSF) abnormalities may be mild and CSF RT-qPCR has limited sensitivity, necessitating parallel serology (e.g., IFAT with confirmatory line blot) and, in some cases, brain biopsy/autopsy with immunohistochemistry or RNA detection[5, 12, 13]. No proven curative therapy exists, although ribavirin and favipiravir have shown in vitro activity and have been used off-label in some cases without clearly established benefit[5, 13, 14]. Public health priorities therefore emphasize clinician awareness, targeted testing in endemic areas, and One Health approaches that integrate wildlife reservoirs and human surveillance, while acknowledging that specific preventive measures are constrained by uncertain transmission pathways[1, 15].
1. Introduction
BoDV-1 has been recognized for decades as the causative agent of Borna disease in animals, a severe and often fatal neurologic disease particularly affecting horses and sheep in endemic regions of Central Europe[5, 9]. In humans, debates about BoDV-1 pathogenicity persisted for years, but human infection was first proven in 2018 and subsequent investigations established BoDV-1 as a cause of severe, frequently fatal encephalitis in Germany[6, 7]. A key turning point in clinical recognition occurred with reports of possible transplant-associated transmission in 2018, in which a cluster of solid organ recipients from a single donor in southern Germany developed acute encephalitis/encephalopathy and two recipients died[16]. This cluster, coupled with subsequent sporadic cases and retrospective confirmations from archived brain tissue, shifted BoDV-1 from a contested association to a molecularly confirmed zoonotic pathogen causing distinctive, highly lethal encephalitis in defined endemic regions[8, 10].
2. Virology and Taxonomy
BoDV-1 is classified within the family Bornaviridae and is described as species Orthobornavirus bornaense in some sources, while other clinical and surveillance literature refers to it as species Mammalian orthobornavirus 1 (or Mammalian 1 orthobornavirus) within the genus Orthobornavirus[1, 2, 17]. Structurally and genomically, BoDV-1 is an enveloped, non-segmented, negative-sense, single-stranded RNA virus within the order Mononegavirales[4, 18]. Its genome is approximately 8.9 kb and has been described as encoding six structural proteins, while an accessory X protein is also reported to have regulatory functions, reflecting the literature’s protein nomenclature across sources[5].
BoDV-1 replication and transcription occur in the host cell nucleus and are associated with persistent infection[4, 5]. Viral proteins discussed in the included sources include the glycosylated membrane protein G mediating entry, the matrix protein M, and the nucleocapsid protein N that binds viral RNA and forms the ribonucleoprotein complex together with phosphoprotein P and the large protein L (RNA-dependent RNA polymerase)[5]. The accessory X protein has been described as having regulatory functions, and sequence divergence analyses have highlighted comparatively higher variability in G and X relative to N, M, and P in available sequence comparisons[5, 19]. In humans and other accidental hosts, BoDV-1 is described as neurotropic, strongly cell-bound, and non-cytopathogenic, with infection reported not only in neurons but also in astrocytes and oligodendrocytes in human disease contexts[10].
3. Natural Reservoir, Geographic Range, and Spillover
The only known natural reservoir host species identified in multiple sources is the insectivorous bicolored white-toothed shrew (Crocidura leucodon)[2, 14]. In reservoir hosts, BoDV-1 infection can be asymptomatic and is associated with shedding in multiple excretions, including saliva, urine, feces, and skin scales, supporting environmental contamination as a plausible interface for spillover[9, 20]. Although the geographic distribution of C. leucodon spans broad temperate zones, BoDV-1 appears endemic only in regional subpopulations within a narrower Central European band, consistent with the restricted distribution of animal and human cases in parts of Germany and neighboring countries[1].
BoDV-1-endemic regions are repeatedly identified in Germany, Switzerland, Austria, and Liechtenstein, and multiple sources emphasize that BoDV-1’s endemic area is “remarkably restricted” to these parts of Central Europe[8, 9]. Within Germany, the endemic region is described as extending from Bavaria in the south to further northern and eastern federal states, and case series have documented that while most human cases are reported from Bavaria, cases have also been described from the north and east of Germany[5, 7]. In individual case investigations, exposures often include rural residence, agricultural work, animal contacts, and peridomestic settings where shrew presence may be suspected but not directly confirmed, underscoring the difficulty of reconstructing specific spillover events[1].
The precise transmission route to humans remains incompletely defined across the included literature, with several sources explicitly stating that the transmission event is unknown or unclear[1, 21]. Hypotheses include uptake of contaminated particles via an olfactory route and peridomestic environmental exposure, while formal evidence for direct shrew-to-human transmission is limited, and sustained human-to-human transmission has not been demonstrated outside transplantation settings[8, 19, 22]. Transplant-associated infection represents a distinct mechanism, as donor-derived BoDV-1 transmission to recipients has been reported and is described as the only confirmed human-to-human transmission route in some summaries[4, 17].
4. Epidemiology and Recognition of Human Disease
BoDV-1’s emergence as a recognized human pathogen is anchored to molecular confirmation and clustered reports in 2018, when Germany reported four human cases of acute encephalitis/encephalopathy associated with BoDV-1, including three cases in a solid organ recipient cluster from a single donor and one additional fatal case in southern Germany[16]. In parallel, clinical and laboratory investigations have emphasized that diagnosis was often made retrospectively in cases occurring before 2018, whereas intra vitam diagnosis became more feasible after 2018 as awareness and testing expanded[12]. The broader implication—that mammalian bornaviruses can cause fatal human encephalitis—was also supported by earlier recognition of VSBV-1 in an encephalitis cluster linked to variegated squirrel breeding in 2015, which contextualized bornaviruses as zoonotic agents beyond classical veterinary disease paradigms[5].
In Germany, surveillance infrastructure expanded when direct detection of zoonotic bornaviruses in human samples became notifiable in 2020 under the Infection Protection Act, and multiple sources link increased awareness and active case finding to increased identification of both retrospective and incident cases[21, 23]. As of early 2023, nearly 50 human BoDV-1 encephalitis cases were registered in Germany, with most detected retrospectively, indicating that historic case ascertainment continues to shape observed incidence patterns[7]. A more recent synthesis reports identification of 50 molecularly confirmed (partially retrospective) sporadic human cases as of December 2024, with a focus on Bavaria, and notes that almost all cases (49/50) were fatal, illustrating the persistently high lethality observed in surveillance data[8].
Although Bavaria remains the predominant locus of reported disease in many datasets, case reports and surveillance summaries document cases outside Bavaria, including a fatal case in Brandenburg in a region previously not known for human infections and additional diagnoses in northern and eastern German states (e.g., Thuringia, Saxony-Anhalt, Lower Saxony) in 2021 among residents of known animal-endemic areas[1, 24]. Epidemiologic interviews and case-control efforts have underscored the challenge of identifying a specific exposure event, with peridomestic shrew presence supporting environmental transmission hypotheses despite absent direct shrew contact reports[3].
The table below summarizes key milestones in recognition and surveillance that are directly supported by the provided sources.
5. Clinical Features
Across multiple case series and reviews, BoDV-1 encephalitis typically begins with a short, non-specific prodrome, often described as flu-like symptoms with fever and headache, followed by neurologic symptoms such as confusion, psychomotor slowing, ataxia, or seizures[10, 25]. Large syntheses report that common early manifestations include drowsiness, fever, and headache, and that a subset of patients experience progressive loss of consciousness or early seizures within the first week of symptom onset[11]. Clinical deterioration is often rapid, with progression to deep coma within days and death after several weeks in many reported cohorts[10].
Time-to-event descriptions illustrate the typical tempo of severe disease, with one clinical analysis reporting that patients required protective intubation around day 13 after symptom onset and died on average around 30 days after onset (range reported as 23–40 days in that cohort)[25]. Another dataset reports a mean of approximately 38 days from symptom onset until death among patients with available data, consistent with the several-week duration highlighted elsewhere[23]. In a broader review of 37 cases, 34/37 patients died, with median survival reported as four weeks after onset of the clinical syndrome, emphasizing the high lethality and relatively short course in most patients[11].
Case-fatality is consistently reported as very high, with multiple sources stating that case fatality rates exceed 90% and surveillance syntheses reporting near-universal fatality in confirmed cases[5, 8]. In a comprehensive compilation of 46 patients with BoDV-1 infection, encephalitis was diagnosed in 45 patients and fatal outcome occurred in 44, corresponding to a known case-fatality rate of 97.8% in that dataset[9]. Survivors are rare and may be left with significant sequelae, including severe disability requiring nursing home care or optic nerve atrophy documented in transplant-associated survival and other case reports[18, 21].
6. Neuropathology and Neuroimaging
Neuropathologically, BoDV-1 encephalitis is described as a non-purulent panencephalitis or panencephalomyelitis characterized by lymphocytic inflammation, perivascular cuffing, and prominent microglial activation across CNS regions, consistent with an immune-mediated disease process in spillover hosts[10, 26]. In systematic autopsy analyses, features include lymphocytic sclerosing panencephalomyelitis with strong formation of microglial nodules, with inflammatory changes in brainstem and spinal cord and milder cerebellar involvement in some series[26]. Classical intranuclear inclusion bodies (Joest-Degen bodies) have been described in human cases, including eosinophilic spherical intranuclear inclusions in neurons and astrocytes reported in autopsy series, although their prominence and detectability can vary across cases and methods[1, 26].
Neuroimaging patterns can support suspicion but are not uniformly present early in disease, and multiple reports emphasize that MRI can be unremarkable in early phases, contributing to diagnostic delay[14, 27]. In one MRI-focused cohort, inflammatory lesions were reported to arise mainly from the head of the caudate nucleus with involvement of adjacent insula, thalamus, and operculum, and diffusion restriction of T2-hyperintense lesions was common while the blood–brain barrier remained intact in most cases[23]. A review of imaging across reported cases similarly notes involvement of diencephalon and basal ganglia, including caudate nucleus head anomalies, as well as insular and temporal pole changes in a subset of patients[11].
Individual cases also demonstrate MRI–pathology dissociation, including reports where repeated MRI scans did not reflect the severity of diffuse panencephalomyelitis demonstrated at autopsy[22]. CSF findings are variable and can be mild or even absent early, with some studies noting that CSF changes may resemble other viral encephalitides and may include only mild lymphocytic pleocytosis, while other cases show progressive pleocytosis and elevated protein and lactate later in the course[12, 22]. These features support the recurrent theme that reliance on early imaging or standard CSF parameters alone may miss BoDV-1 encephalitis at a treatable diagnostic window[5, 8].
7. Diagnosis
Antemortem diagnosis of BoDV-1 encephalitis is widely described as challenging due to non-specific early symptoms, late seroconversion, and limited sensitivity of RT-qPCR from CSF relative to brain tissue, prompting recommendations for combined, repeated testing approaches[5, 12]. Molecular confirmation can be achieved by qRT-PCR detecting BoDV-1 RNA in CSF, brain biopsy, or autopsy tissue, and some case series describe that confirmed diagnosis requires detection of BoDV-1-specific RNA or proteins, reflecting graded case definitions used in Germany[5, 10]. Because viral RNA loads in CSF are relatively low, RT-qPCR from CSF may have only limited sensitivity and sometimes necessitates brain biopsy or post mortem tissue to fulfill confirmed-case definitions, reinforcing parallel serologic testing strategies[5].
Serologic workflows used in endemic settings commonly include indirect immunofluorescence assay (IFAT) screening with confirmatory testing such as line blot, and multiple sources describe these as established diagnostic tools for BoDV-1[13, 14]. In a diagnostic performance analysis, specificity of IFAT and line blot from serum and CSF, as well as PCR testing from CSF, was reported as 100%, while sensitivity for PCR in CSF was variable (reported as 25–67%), supporting the practice of combining molecular and serologic methods in suspected cases[28]. Serology may become positive only after disease onset, with antibodies detected as early as 12 days after symptom onset in one study and seroconversion occurring later in some individual cases, reinforcing the need for repeated sampling when suspicion persists[14, 28].
Histopathologic and tissue-based confirmation approaches include immunohistochemistry for BoDV-1 antigens and in situ hybridization for viral RNA, and these methods have been used both in retrospective investigations and in transplant-associated cases where metagenomic sequencing assembled nearly complete BoDV-1 genomes from brain biopsy or autopsy samples[1, 17]. In a retrospective fatal encephalitis case in Brandenburg, BoDV-1 was demonstrated by RT-qPCR in multiple brain regions from FFPE samples with high viral loads and supported by immunohistochemistry and in situ hybridization that showed predominantly nuclear signals for viral genomic RNA and mRNA[1]. Collectively, these findings support a diagnostic principle emphasized across sources: testing should be guided by clinical and epidemiologic suspicion, including residence in or travel to endemic areas and compatible encephalitis syndromes of unknown etiology after standard panels are negative[20, 29].
8. Treatment and Outcomes
Across case series and reviews, there is no established or proven curative therapy for BoDV-1 encephalitis, and multiple sources emphasize the absence of causal treatment alongside extremely high fatality[8, 14]. Antivirals such as ribavirin and favipiravir have demonstrated in vitro activity against bornaviruses, and off-label use has been attempted in some patients, including combination regimens initiated after molecular diagnosis in selected cases[13, 14]. However, a synthesis of clinical experience indicates that sustainable clinical improvement under experimental therapy has generally not been observed, likely influenced by late diagnosis and advanced disease state at treatment initiation[15].
Empiric therapies directed at alternative encephalitis etiologies are common before diagnosis, including antiviral (e.g., acyclovir) and immunomodulatory regimens (e.g., high-dose corticosteroids) given under presumptive diagnoses such as autoimmune or paraneoplastic encephalitis, illustrating how clinical uncertainty can delay targeted testing and experimental treatment attempts[1, 22]. In one detailed report, favipiravir was initiated late in the clinical course (day 36) without clinical improvement, and the patient died on day 43, consistent with the frequent mismatch between recognition and the rapid evolution to irreversible brain injury[6]. Immunosuppressive strategies have been discussed as a potential therapeutic angle in immune-mediated pathology, with some studies noting that immunosuppression might decelerate disease course and rodent models suggesting T-lymphocyte suppression can prevent immunopathology, but these observations have not yet translated into evidence-based human treatment recommendations[26].
Outcome data remain dominated by fatality, with surveillance and review datasets reporting case-fatality rates above 90% and near-universal death in confirmed cases, including 49/50 fatal cases in one surveillance synthesis and 34/37 deaths in a literature review cohort[8, 11]. When survival occurs, severe long-term sequelae are reported, such as optic nerve atrophy in a transplant recipient in remission and permanent disability in an acute case diagnosed in 2021, emphasizing that “survival” often entails substantial neurologic burden[17, 24].
9. Public Health, Prevention, and Surveillance
Public health responses to BoDV-1 encephalitis in Germany have included enhanced surveillance through mandatory reporting of direct pathogen detection introduced in 2020, which multiple sources link to improved case finding and better characterization of incidence patterns in endemic areas[8, 21]. Awareness campaigns aimed at clinicians, diagnostic laboratories, and neuropathologists have also been implemented, including a nationwide clinician awareness campaign described in 2019 that preceded detection of acute cases during routine diagnostics in 2021, illustrating how communication can influence case ascertainment for rare diseases[21]. Some surveillance-oriented reports note that detected cases are notified to local health authorities immediately, supporting rapid public health situational awareness once laboratory confirmation is obtained[13].
Prevention is constrained by uncertainty about transmission events and routes, and several sources explicitly state that it is challenging to propose preventive measures because transmission likely occurs covertly in peridomestic settings and may be indirect from environments contaminated with shrew excretions[8, 15]. As vaccines are not available for this nearly uniformly fatal disease and exposure events are often elusive, proposed prophylactic approaches emphasize reducing exposure to the reservoir, improving awareness among clinicians and veterinarians, and visualizing risk areas to implement practical measures that reduce reservoir exposure in affected regions[9]. In the transplantation context, ECDC and other assessments emphasize that transplantation professionals and clinicians should be aware of possible BoDV-1 related encephalitis and potential transmission through donated organs, especially in endemic areas, reflecting the sentinel role of transplant-associated cases in recognizing human risk[16, 18].
Open Questions and Future Directions
A consistent theme across epidemiologic, clinical, and public health sources is that transmission routes to humans remain unclear or uncertain, with many investigations unable to identify discrete exposure events despite reservoir identification and peridomestic risk hypotheses[3, 8]. This uncertainty complicates targeted prevention and post-exposure prophylaxis planning, with authors explicitly stating that formulating indications for post- or pre-exposure prophylaxis seems impossible for BoDV-1 given that exposure events usually remain elusive[8, 20]. It also motivates the need for continued One Health research that integrates reservoir ecology, environmental exposure pathways, and improved diagnostic surveillance to refine risk maps and understand why human cases appear clustered geographically and remain rare despite reservoir presence[1, 9].
Therapeutically, there is a recognized need for studies evaluating viral suppression strategies and combination approaches that might integrate antiviral agents with immunomodulation, reflecting both the immune-mediated neuropathology described in spillover hosts and the limited success of late experimental therapy in advanced disease[15, 25]. Vaccine development faces conceptual and practical challenges related to target population size and the rarity of human disease, including estimates that millions of rural residents could theoretically be at risk while the number needed to vaccinate to prevent a single case would be very large, implying that any human vaccine would require an exceptionally high safety profile and extensive testing[8].
Conclusion
BoDV-1 is now established as a zoonotic bornavirus capable of causing severe and frequently fatal human encephalitis in Central Europe, with recognition accelerated by molecular confirmation and sentinel events such as transplant-associated transmission clusters reported in 2018[1, 16]. The reservoir in Crocidura leucodon is well supported, and endemic regions are relatively circumscribed, but the precise spillover mechanisms to humans remain uncertain, limiting the specificity of preventive guidance beyond awareness, targeted testing, and reduction of reservoir exposure where feasible[2, 8]. Given the consistently high case-fatality reported across cohorts and surveillance datasets and the absence of proven therapy, earlier recognition through combined molecular and serologic diagnostics in endemic contexts remains a critical near-term priority while research addresses transmission, pathogenesis, and effective countermeasures[5, 8].
