Human Borna Disease Virus 1: An emerging neurotropic virus of
concern
Michaela Cain and Hinh Ly*
Department of Veterinary & Biomedical Sciences, College of Veterinary
Medicine, University of Minnesota, Twin Cities, MN, USA
*Address correspondences to:
Hinh Ly, Ph.D.
University of Minnesota, Twin Cities, 1988 Fitch Ave., Ste. 295, St
Paul, MN 55108
Phone: 612-625-3358
E-mail address: hly@umn.edu
Word counts: 846
Key Words: Human Borna Virus Disease 1, BoDV-1, encephalitis,
neurotropic RNA virus
To the Editor:
Human Borna disease virus 1, BoDV-1, is a negative sense,
single-stranded, enveloped RNA virus in the family Bornaviridaewithin the order Mononegavirales1,2. The viral genome
has six known open reading frames that produce at least six proteins:
nucleoprotein (N), phosphoprotein (P), putative matrix protein (M), type
1 membrane glycoprotein (G), and putative viral polymerase
(L)2,3. Unique among all known RNA viruses, the
replication and transcription process of BoDV-1 occurs in the host
cell’s nucleus and its genome is highly conserved2.
BoDV-1 has been shown to replicate in cells of the central nervous
system, including neurons, astrocytes and oligodendrocytes. The
bicolored white-toothed shrew is the primary animal reservoir for
BoDV-1, which can establish a persistent infection with broad tissue
tropism, but without an overt clinical disease4.
BoDV-1 infection is characterized by immune mediated meningoencephalitis
that can often lead to severe complications and death in spillover
hosts, such as horses and sheep4. BoDV-1 has also been
found to induce behavioral changes in the animals, such as anxiety,
aggression, cognitive defects, and hyperactivity in these animals and
can lead to a form of neurotropic disease that is characterized by T
lymphocyte-mediated encephalitis4. Borna disease in
horses has been described since the 18th century, but
only in 1885 that it was designated Borna disease following a major
horse epidemic in Borna, which is a town in Saxony,
Germany5,6. It is noteworthy that BoDV-1 has
predominantly been found in regions of Germany, Liechtenstein
(Switzerland), and Austria7. It is thought that some
livestock can serve as intermediary hosts of BoDV-1; however, zoonotic
transmissions of BoDV-1 have been suspected but not definitely
confirmed.
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 have not been definitively
confirmed7. In a recent report published in the
Emerging Microbes & Infection journal8, Frank and
colleagues developed and validated a workflow for rapid testing of
BoDV-1 infections using serum and cerebrospinal fluid from at risk
patients. 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
postmortem 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 Germany8.
The first human case of Borna disease that was serologically confirmed
was reported in 1980s9. A recent study by Liesche and
colleagues identified six cases of BoDV-1 infection in 6 females (17-65
years old) from 1999-2019, in brain tissue of encephalitis cases
isolated in Bavaria, Germany10. All patients developed
headache, fever, confusion, deep comas, and died within two 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 fatal4.
Another study done in Germany from 2018-2020 examined 103 encephalitis
cases of unknown etiology using qRT-PCR on CSF and brain tissues and
found 3% prevalence of BoDV-1 infections11. All
patients were from Bavaria, who developed encephalitis and fevers, and
died within a month of the onset of symptoms (Table 1). 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 harbor
BoDV-1 antibodies, which were tested serologically through fluorescence
antibody tests and line blots7. 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. Due to the seemingly
sporadic nature of BoDV-1 infections, it has been hypothesized that each
human case represents an independent zoonotic transmission event.
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 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, which can
lead to very high and rapid mortality rate. Using new molecular tools,
such as the reverse genetics system for BoDV-11,
researchers have started to make some inroads into understanding the
basic biology of this virus. Until more epidemiological, gross- and
histo-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.