Increasing evidence of human infections by the neurotropic Borna disease virus 1 (BoDV-1)

Due to relatively rare instances of human infections by the Borna disease virus 1 (BoDV-1) and the difficulty of developing and validating a test for diagnosing it, human cases of fatal encephalitis caused by BoDV-1 have been difficult to confirm. Zoonotic transmissions of BoDV-1 have also been suspected but have not been definitively ascertained. Using serum and cerebrospinal fluid of at-risk patients, who were living in northern and eastern parts of Germany, the authors of a recent study1 successfully developed and validated a new workflow for rapid testing of BoDV-1 infections in humans. Using next-generation sequencing method, they were able to recover the full-length BoDV-1 genome from the patient's brain tissue that phylogenetically match the viral sequences to BoDV-1 strains found in shrews and domesticated animals, implicating zoonotic transmissions of this virus. This editorial aims to raise awareness about this emerging neurotropic virus that might have important public health implications.

in the Czech Republic have been associated with subclinical BoDV-1 infections [6].
The first suspected human cases of Borna disease encephalitis were reported in 1980s. Since then, it has been theorized that a substantial proportion of unidentified human fatal encephalitis cases are caused by BoDV-1, but due to difficulties in developing and validating a test for diagnosing BoDV-1 infection, human cases of BoDV-1 associated encephalitis have not been definitively confirmed [9]. Frank and colleagues have successfully developed and validated a new workflow for rapid testing of BoDV-1 infections using serum and cerebrospinal fluid from at risk patients [1]. The serological workflow uses an indirect immunofluorescence assay followed by a line blot assay, and utilizes the BoDV-1 phosphoprotein (P) antigen. In addition, qRT-PCR and next-generation sequencing were conducted on some patients, who tested positive serologically for BoDV-1 infection. The authors also conducted histopathological characterization of positively confirmed BoDV-1 post-mortem cases. Using these methods, they were able to recover the full-length BoDV-1 genome from the patient's brain tissue, and upon sequencing the viral genome, they were able to phylogenetically match the viral sequences to BoDV-1 strains found in shrews and domesticated animals of cluster 4 in central Germany [10].
Another study by Liesche and colleagues identified six cases of BoDV-1 infection in six females (17-65 years old) from 1999 to 2019, in brain tissue of encephalitis cases isolated in Bavaria, Germany [11]. All patients developed headache, fever, confusion, deep comas, and died within 2 months of symptom onset (Table 1). In addition, Niller and colleagues reported three previously known cases of encephalitis caused by BoDV-1 in solid-organ transplant, two of which were fatal [5]. Another study done in Germany from 2018 to 2020 examined 103 encephalitis cases of unknown aetiology using qRT-PCR on CSF and brain tissues and found 3% prevalence of BoDV-1 infections [12]. All patients were from Bavaria, who developed encephalitis and fevers, and died within a month of the onset of symptoms. Although more studies need to be done, these recent reported cases suggest an increased risk of BoDV-1 infections in Germany and the potential for severe outcomes in patients who contract the virus.
Interestingly, people who lived with and had been in close contact with infected patients neither showed signs of disease nor did they harbour BoDV-1 antibodies, which were tested serologically through fluorescence antibody tests and line blots [9]. The only confirmed human-to-human transmission of BoDV-1 was through solid organ transplantation, and it is theorized that all other human cases are spillover events from BoDV-1 infected animals. It has been hypothesized that each human case represents an independent zoonotic transmission event. However, the presence of asymptomatic BoDV-1 carriers in different parts of the world argues for a potential direct transmission of the virus between humans.
There are significant gaps in knowledge about this virus, e.g. how it transmits within and between animal species (intraspecies and interspecies transmissions), and how it can cause disease (disease pathogenesis and pathology), etc. Although the incidence of Borna disease encephalitis seems to be relatively low and is localized to some endemic regions in the world, it is important to conduct routine serological surveys of the virus and to study the disease that it causes that can lead to very high and rapid mortality rate. In addition, its potential link to psychiatric disorders and its increasing geographic presence emphasize the need to study this virus further. Using new molecular tools, such as the reverse genetics system for BoDV-1 [2], researchers have started to make some inroads into understanding the basic biology of this virus. However, until more epidemiological, pathological, virological, and immunological studies are done on BoDV-1 and the disease that it causes in humans, no prophylactic and therapeutic modalities can be developed to prevent or treat these emerging and fatal human viral infections.

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Funding
The authors reported no funding associated with the work featured in this article.

Data Availability statement
No primary/research data are included in this article.