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\begin{document}

\title{Human Borna Disease Virus 1: An emerging neurotropic virus of concern}



\author[1]{Hinh Ly}%
\author[1]{Michaela Cain}%
\affil[1]{University of Minnesota Twin Cities}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\textbf{Letter to the editor}

\textbf{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
\emph{Bornaviridae}within the order
Mononegavirales\textsuperscript{1,2}. 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)\textsuperscript{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 conserved\textsuperscript{2}.
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 disease\textsuperscript{4}.
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 sheep\textsuperscript{4}. 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 encephalitis\textsuperscript{4}. Borna disease in
horses has been described since the 18\textsuperscript{th} century, but
only in 1885 that it was designated Borna disease following a major
horse epidemic in Borna, which is a town in Saxony,
Germany\textsuperscript{5,6}. It is noteworthy that BoDV-1 has
predominantly been found in regions of Germany, Liechtenstein
(Switzerland), and Austria\textsuperscript{7}. 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
confirmed\textsuperscript{7}. In a recent report published in the
Emerging Microbes \& Infection journal\textsuperscript{8}, 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 Germany\textsuperscript{8}.

The first human case of Borna disease that was serologically confirmed
was reported in 1980s\textsuperscript{9}. 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, Germany\textsuperscript{10}. 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 fatal\textsuperscript{4}.
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 infections\textsuperscript{11}. 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 blots\textsuperscript{7}. 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-1\textsuperscript{1},
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.\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
\begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Patient Age}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Patient Gender}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Location}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Profession}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Time}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Symptoms}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Outcome}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Reference}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
55\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Bavaria\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Part-time cleaner\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Mid- January 2019\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
encephalitis, fever, headache, and coma\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death 3 weeks after onset of symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
rural Bavaria\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
unknown\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
November 2019\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
encephalitis, fever, headache, and epileptic seizures\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death 4 weeks after onset of illness\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
79\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
rural Bavaria\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Farmer\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
June 2020\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
encephalitis, fever, and confusion\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death 4 weeks after the onset of symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
74\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Bavaria\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Axonal motor neuropathy with Guillain-Barr\selectlanguage{ngerman}é syndrome-like spread\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death 14 weeks after onset of symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Bavaria\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Fever, memory deficits, epileptic seizures, progressive loss of
consciousness\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death 5 weeks after onset of symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Bavaria\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Fever, Slurred speech, progressive loss of consciousness\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death 4 weeks after onset of symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Bavaria\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Fever, headache, confusion, progressive loss of consciousness\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death 6 weeks after onset of symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
78\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Bavaria\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Right-sided weakness, epileptic seizures, progressive loss of
consciousness\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death 4 weeks after onset of symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
55\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Bavaria\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Fever, headache, amnesic aphasia, progressive loss of
consciousness\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death 2 weeks after onset of symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

*Not all patient data was available

Disclosure statement: No potential conflict of interest was reported by
the authors.

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

Acknowledgments: None

Data availability statement: No primary data are included in this
article.

References cited:

1. Perez M, Sanchez A, Cubitt B, Rosario D, de la Torre JC. A reverse
genetics system for Borna disease virus. J Gen Virol. Microbiology
Society,; 2003;84(11):3099--3104.

2. Jordan I, Lipkin WI. Borna disease virus. Rev Med Virol. 2001
Jan;11(1):37--57.

3. Walker MP, Jordan I, Briese T, Fischer N, Lipkin WI. Expression and
Characterization of the Borna Disease Virus Polymerase. J Virol. 2000
May;74(9):4425--4428. PMCID: PMC111960

4. Niller HH, Angstwurm K, Rubbenstroth D, Schlottau K, Ebinger A, Giese
S, Wunderlich S, Banas B, Forth LF, Hoffmann D, H\selectlanguage{ngerman}öper D, Schwemmle M,
Tappe D, Schmidt-Chanasit J, Nobach D, Herden C, Brochhausen C,
Velez-Char N, Mamilos A, Utpatel K, Evert M, Zoubaa S, Riemenschneider
MJ, Ruf V, Herms J, Rieder G, Errath M, Matiasek K, Schlegel J,
Liesche-Starnecker F, Neumann B, Fuchs K, Linker RA, Salzberger B,
Freilinger T, Gartner L, Wenzel JJ, Reischl U, Jilg W, Gessner A,
Jantsch J, Beer M, Schmidt B. Zoonotic spillover infections with Borna
disease virus 1 leading to fatal human encephalitis, 1999--2019: an
epidemiological investigation. Lancet Infect Dis. 2020 Apr
1;20(4):467--477.

5. Rott R, Becht H. Natural and Experimental Borna Disease in Animals.
In: Koprowski H, Lipkin WI, editors. Borna Dis {[}Internet{]}. Berlin,
Heidelberg: Springer; 1995 {[}cited 2023 Mar 5{]}. p. 17--30. Available
from: https://doi.org/10.1007/978-3-642-78618-1\_2

6. Nobach D, Müller J, Tappe D, Herden C. Chapter Five - Update on
immunopathology of bornavirus infections in humans and animals. In: Carr
JP, Roossinck MJ, editors. Adv Virus Res {[}Internet{]}. Academic Press;
2020 {[}cited 2023 Mar 5{]}. p. 159--222. Available from:
https://www.sciencedirect.com/science/article/pii/S0065352720300221

7. Tappe D, Pörtner K, Frank C, Wilking H, Ebinger A, Herden C, Schulze
C, Muntau B, Eggert P, Allartz P, Schuldt G, Schmidt-Chanasit J, Beer M,
Rubbenstroth D. Investigation of fatal human Borna disease virus 1
encephalitis outside the previously known area for human cases,
Brandenburg, Germany -- a case report. BMC Infect Dis. 2021 Aug
10;21(1):787.

8. Frank C, Wickel J, Brämer D, Matschke J, Ibe R, Gazivoda C, Günther
A, Hartmann C, Rehn K, Cadar D, Mayer TE, Pörtner K, Wilking H,
Schmidt-Chanasit J, Tappe D. Human Borna disease virus 1 (BoDV-1)
encephalitis cases in the north and east of Germany. Emerg Microbes
Infect. Taylor \& Francis; 2022 Dec 31;11(1):6--13. PMID: 34783638

9. Carbone KM. Borna Disease Virus and Human Disease. Clin Microbiol
Rev. 2001 Jul;14(3):513--527. PMCID: PMC88987

10. Liesche F, Ruf V, Zoubaa S, Kaletka G, Rosati M, Rubbenstroth D,
Herden C, Goehring L, Wunderlich S, Wachter MF, Rieder G, Lichtmannegger
I, Permanetter W, Heckmann JG, Angstwurm K, Neumann B, Märkl B, Haschka
S, Niller HH, Schmidt B, Jantsch J, Brochhausen C, Schlottau K, Ebinger
A, Hemmer B, Riemenschneider MJ, Herms J, Beer M, Matiasek K, Schlegel
J. The neuropathology of fatal encephalomyelitis in human Borna virus
infection. Acta Neuropathol (Berl). 2019;138(4):653--665. PMCID:
PMC6778062

11. Eisermann P, Rubbenstroth D, Cadar D, Thomé-Bolduan C, Eggert P,
Schlaphof A, Leypoldt F, Stangel M, Fortwängler T, Hoffmann F, Osterman
A, Zange S, Niller HH, Angstwurm K, Pörtner K, Frank C, Wilking H, Beer
M, Schmidt-Chanasit J, Tappe D. Active Case Finding of Current
Bornavirus Infections in Human Encephalitis Cases of Unknown Etiology,
Germany, 2018--2020. Emerg Infect Dis. 2021 May;27(5):1371--1379. PMCID:
PMC8084505

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