A Century-Long Journey from Animal Plague to Human Enigma
For over a century, a mysterious and fatal illness haunted the horses and sheep of Central Europe. Farmers in the Saxon town of Borna, Germany, witnessed their animals develop dramatic behavioral changes—compulsive movements, hyperactivity, and aggression—followed by progressive neurological decline and death. The 1885 epidemic that swept through the town's stables would give this enigmatic condition its name: Borna disease. It would take more than one hundred years of scientific investigation to reveal its cause—the Borna Disease Virus (BDV)—and to make the startling discovery that this pathogen could also invade human brains, with fatal consequences 3 4 .
First identified in horses in Borna, Germany in 1885, giving the virus its name.
Confirmed as a human pathogen in 2018, causing fatal encephalitis.
The story of Borna disease virus represents a fascinating chapter in modern medicine, spanning veterinary science, virology, and human neurology. This narrative stretches from its identification as an infectious agent in 1929, through its classification as a unique RNA virus in 1990, to the recent confirmation that it can cause fatal encephalitis in humans 3 4 . BDV has repeatedly challenged scientific assumptions with its unconventional biology, including its preference for the nucleus—a trait rare among RNA viruses—and its ability to establish persistent infections that manipulate host behavior without directly destroying cells 6 . This article traces the remarkable scientific journey to understand this elusive pathogen, exploring how a veterinary plague transformed into a human health concern and what its study reveals about the delicate interface between animal reservoirs and human disease.
Borna disease virus stands apart from most known viruses due to its unique biological properties. As a negative-sense, single-stranded RNA virus with a genome consisting of at least six open reading frames that produce proteins N, P, M, G, L, and p10, BDV initially appeared similar to other members of the Mononegavirales order 3 . However, closer examination revealed striking differences that eventually justified its classification in a separate family—the Bornaviridae 6 .
Unlike other non-segmented negative-strand RNA viruses that replicate in the cytoplasm, BDV is the only known animal virus of this class that replicates inside the nucleus of infected cells 3 . This unusual localization requires the virus to exploit the host's nuclear transport machinery.
The physical structure of BDV particles remained elusive for decades due to their cell-associated nature and low yield in tissue culture. Eventually, electron microscopy studies revealed spherical, enveloped particles approximately 130 nm in diameter 6 .
BDV establishes persistent, non-cytolytic infections primarily in neural cells—neurons, astrocytes, and oligodendrocytes—though it can also infect non-neural tissues including blood, thymus, and bone marrow, especially under conditions of immunosuppression 3 . The virus's ability to infect the nervous system without directly killing cells allows it to maintain long-term infections while avoiding immune detection, contributing to its mysterious disease patterns.
The recognition of Borna disease as a distinct entity emerged from veterinary medicine. The severe 1885 outbreak in Borna, Germany, prompted systematic studies that confirmed the infectious nature of the disease by 1929, though the pathogen itself remained unidentified for decades 3 . For years, BDV was believed to primarily affect horses and sheep in limited geographic regions of Central Europe 3 .
Severe outbreak in Borna, Germany gives the disease its name
Infectious nature of the disease confirmed, though pathogen remains unidentified
Causative agent identified as a novel RNA virus 3
The late 20th century brought revolutionary discoveries. In 1990, the causative agent was finally identified as a novel RNA virus 3 , and subsequent research revealed a much broader host range, including cattle, goats, rabbits, cats, and various bird species 3 . The geographic distribution also expanded beyond Central Europe to include the United Kingdom, Japan, Israel, Australia, and the United States 3 .
The potential for human infection became one of the most controversial aspects of BDV research. Initial evidence emerged from serological studies in the 1980s, followed by detection of viral antigens and RNA in patients with neuropsychiatric disorders 3 6 . However, the scientific community remained skeptical due to technical difficulties in validating diagnostic tests and reproducing results across laboratories 3 .
>97%
Among symptomatic patients
Data based on reports to German health authorities
The landmark confirmation of BDV as a human pathogen came in 2018, when two independent studies demonstrated the presence of BDV antigen and RNA in encephalitis patients, including organ transplant recipients and a healthy young man 2 4 . This breakthrough established BDV-1 (BoDV-1) as a zoonotic pathogen causing fatal encephalitis in humans 2 4 . Researchers subsequently identified the bicolored white-toothed shrew (Crocidura leucodon) as the natural reservoir host, in which the virus establishes a productive infection not limited to the nervous system, allowing viral shedding through saliva, urine, and feces 4 .
To date, molecular epidemiological studies have confirmed that the endemic area for BoDV-1 is remarkably restricted to parts of Germany, Austria, Switzerland, and Liechtenstein, consistent with the distribution of the reservoir host 4 . As of early 2025, 50 laboratory-confirmed BoDV-1 encephalitis cases have been reported to German health authorities, with an annual incidence of 5-10 infections . The disease progression is typically rapid and fatal, with a mortality rate exceeding 97% among symptomatic patients, creating an urgent need for effective diagnostics and treatments 4 .
While much attention has focused on BoDV-1, its close relative BoDV-2 remained poorly understood due to limited isolations. A pivotal 2025 study published in npj Viruses sought to change this by re-evaluating BoDV-2's genome and establishing a reverse genetics system to investigate its virological properties 2 .
The research team began by reassessing the complete genome sequence of BoDV-2 isolate No/98 using shotgun sequencing of total RNA from persistently infected Vero cells. Comparing their results to the published reference sequence revealed several critical differences, including two nonsynonymous nucleotide substitutions in the L gene (which encodes the RNA-dependent RNA polymerase), and additional single-nucleotide polymorphisms (SNPs) in both the L and P genes 2 .
To determine whether these genetic variations affected viral function, the team constructed cDNA expression plasmids containing each nucleotide substitution independently and in combination. They then employed:
The experiments yielded several crucial findings. First, the researchers demonstrated that one specific nucleotide substitution at position 2762 of the L gene was essential for restoring polymerase activity 2 . BoDV-2 L with the reference sequence showed no polymerase activity in minireplicon assays, while the variant with the corrected nucleotide displayed robust activity 2 .
Second, they successfully rescued infectious rBoDV-2 containing the critical nucleotide substitution. Interestingly, viruses possessing both identified substitutions (at positions 2762 and 3334) were recovered approximately 80 times more efficiently than those with only the essential substitution, suggesting cooperative effects on viral fitness 2 .
Perhaps the most intriguing discovery was that BoDV-2 does not induce superinfection exclusion in persistently infected cells. This means that cells already infected with BoDV-2 can be reinfected with a second virus, allowing low-fitness genome variants to persist through complementation rather than being outcompeted 2 .
| Nucleotide Position | Reference Sequence | Corrected Sequence | Amino Acid Change | Functional Impact |
|---|---|---|---|---|
| 2762 | U | G | Leucine → Arginine at position 921 | Essential for polymerase activity |
| 3334 | U | G | Cysteine → Glycine at position 1112 | Enhances viral recovery efficiency |
| 3743 | SNP | SNP | Nonsynonymous change in C-terminal domain | Affects growth ability |
| 4250 | SNP | SNP | Nonsynonymous change in C-terminal domain | Affects growth ability |
Table 1: Key genetic corrections in BoDV-2 L gene and their functional impacts 2
| Virus Construct | Nucleotide at Position 2762 | Nucleotide at Position 3334 | Polymerase Activity | Virus Recovery | Relative Recovery Efficiency |
|---|---|---|---|---|---|
| Reference | U | U | None | No | 0 |
| BoDV-2 LG | U | G | None | No | 0 |
| BoDV-2 LR | G | U | Restored | Yes | 1x |
| BoDV-2 LRG | G | G | Restored | Yes | ~80x |
Table 2: Recovery efficiency of recombinant BoDV-2 variants showing the critical importance of nucleotide corrections 2
Visualization of relative recovery efficiency for different BoDV-2 constructs 2
This research fundamentally advanced our understanding of bornaviruses by providing a functional reverse genetics system for BoDV-2, correcting critical errors in the published genome sequence, and revealing a novel mechanism for maintaining genetic diversity through the absence of superinfection exclusion. These findings not only characterize BoDV-2's virological properties but also shed light on how bornaviruses persist and evolve in infected hosts 2 .
The study of Borna disease virus requires specialized reagents and techniques to detect, analyze, and combat this elusive pathogen. Modern BDV research employs a diverse toolkit spanning molecular detection, serological assays, and experimental therapeutics.
| Research Tool | Specific Examples | Primary Function | Application Context |
|---|---|---|---|
| Molecular Detection Kits | BDV RT-PCR Kit (Creative Biolabs) | Detection of BDV RNA using reverse transcription PCR | Research-based pathogen detection 1 |
| Borna Disease Virus Probe qRT-PCR Kit (Biofargo) | Quantitative detection of BDV DNA in real-time PCR using hydrolysis probes | Veterinary diagnostics, research applications 5 | |
| Serological Assays | Human Borna disease Virus IgG (BDV-IgG) ELISA Kit (Abbexa) | Detection of BDV-specific IgG antibodies in human samples | Seroprevalence studies, past infection assessment 7 |
| Experimental Therapeutics | Favipiravir (T-705) | Broad-spectrum inhibitor of viral RNA polymerase | Experimental treatment of BoDV-1 encephalitis |
| Cell Culture Systems | Persistently BDV-infected MDCK cells | In vitro model for studying viral replication and morphogenesis | Basic virology research, drug screening 6 |
Table 3: Essential research reagents and solutions for Bornavirus research 1 5 6 7
Diagnostic capabilities have evolved significantly since the early days of BDV research. Contemporary RT-PCR kits provide sensitive detection of viral RNA, with some assays capable of detecting as few as 100 copies per reaction 1 5 . These tools have been essential in confirming BDV infections in both animals and humans, with different assays showing variable performance depending on sample type (fresh-frozen versus formalin-fixed paraffin-embedded tissue) 4 .
Therapeutic development represents perhaps the most urgent area of BDV research. Recent studies have established favipiravir as a promising antiviral candidate, demonstrating in vitro activity against BoDV-1 with a half-maximal inhibitory concentration (IC50) of 319 ± 99 μM . Early therapeutic drug monitoring has confirmed that orally administered favipiravir reaches the cerebrospinal fluid in BoDV-1 encephalitis patients, though current dosing regimens may be insufficient to achieve effective concentrations at the site of infection .
Comparison of favipiravir concentrations achieved in cerebrospinal fluid (CSF) versus the effective IC50 for BoDV-1 inhibition
The century-long scientific journey to understand Borna disease virus illustrates how a veterinary pathogen can gradually reveal its significance for human health. From its origins as the cause of a mysterious equine illness in 19th century Germany, BDV has emerged as a zoonotic agent capable of causing fatal encephalitis in humans 4 8 . This path has been marked by groundbreaking discoveries—from the identification of its unique nuclear replication strategy to the recent confirmation of its reservoir host and transmission patterns 3 4 6 .
Despite these advances, significant challenges remain. The devastating case fatality rate of human BoDV-1 encephalitis demands urgent development of effective treatments, while the restricted endemic area focused in Central Europe necessitates targeted surveillance and awareness 4 .
The recent establishment of reverse genetics systems for bornaviruses and the identification of favipiravir as a promising antiviral candidate provide hope that medical interventions may soon match our scientific understanding 2 .
The story of Borna disease virus serves as a powerful reminder that the boundary between animal and human pathogens is often permeable. As research continues to unravel the complexities of this unique virus, each discovery not only enhances our ability to combat BDV itself but also contributes to the broader understanding of neurotropic infections and the delicate balance between persistent viral infection and immune-mediated pathology. In the silent war between pathogen and host, BDV has proven to be one of the most intriguing adversaries—and its full story is still being written.