Research Projects - Virology

Epidemiology and immunology of human bornavirus encephalitis

Human bornavirus encephalitis is a severe disease caused by two related zoonotic members of the Bornaviridae family, the emerging Borna disease virus 1 (BoDV-1; species Mammalian 1 orthobornavirus), and the rarely detected variegated squirrel bornavirus 1 (VSBV-1; species Mammalian 2 orthobornavirus). While human BoDV-1 encephalitis cases are increasingly detected and have been described in regions endemic for animal Borna disease (BD) in Germany, human VSBV-1 infection is so far limited to five confirmed cases in private holdings and zoological gardens, and acquired through contact to exotic squirrels. The portal of entry and the respective transmission routes to humans are unknown and subject to ongoing research studies.

The group is part of ZooBoCo (Zoonotic Bornavirus Consortium), a BMBF-funded research network, and conducts molecular, epidemiological and immunological studies on human bornavirus encephalitis. For a list of the group's publications about bornavirus encephalitis, click here. For more background information, and details for diagnostic procedures, follow this link (in German).

Borna disease virus 1 (BoDV-1)

For a long time, BoDV-1 has been noted to cause animal BD, a non-purulent meningomyelo-encephalitis of mainly horses and sheep in endemic regions of Germany, Liechtenstein, Switzerland and Austria. BoDV-1 is harbored by at least the insectivorous bicolored white-toothed shrew (Crocidura leucodon) as a natural reservoir. The shrews are asymptomatic and shed the virus by feces and urine. In 2018, the severe pathogenic potential of BoDV-1 for humans became apparent in a cluster of transplant-related BoDV-1 encephalitis cases in Germany with two fatalities; simultaneously, one sporadic unrelated fatal case was detected. Since then, more than 40 sporadic cases, some acute and some retrospectively diagnosed, have been published and/or were notified to public health authorities. It is suspected that most patients become infected close to their rural places of residence.

Variegated squirrel bornavirus 1 (VSBV-1)

VSBV-1 was detected in 2015 as the cause of fatal encephalitis in three private breeders of exotic variegated squirrels (Sciurus variegatoides) in the East of Germany. In 2018 and 2021, VSBV-1 was found to be responsible for the fatal encephalitis of two zoo animal caretakers in the North of Germany who had cared for another exotic squirrel species, Prevost’s squirrels (Callosciurus prevostii). Investigations in private holdings and zoological gardens in Germany and elsewhere in Europe revealed VSBV-1 detection rates of 1.5% - 8.5% in captive exotic squirrels. The animals are asymptomatic and show high viral loads in the brain, kidneys, urinary bladder, skin, and oral cavity, thus qualifying them as potential natural reservoirs. The origin of the virus and its route of introduction into the captive squirrel populations in Europe remained to be elucidated.


Epidemiological studies of BoDV-1 encephalitis

Several retrospective and prospective studies for active case finding, as well as cross-sectional studies for seroprevalence investigations were conducted, employing validated testing schemes and adhering to specific case definitions.

 

 

Human BoDV-1 cases appear rare, even in endemic areas, but show a high case-fatality ratio. Among several hundred tested human patients, BoDV-1 infections were only detected among those with encephalitis and not in patients suffering from other, partly unspecified, diseases.

 

Virus sequences from patients matched closely those from shrew reservoirs, revealing several viral clusters within the BD endemic area and reflecting spill-over transmission close to the patient’s often rural place of residence. How and where these transmission events exactly occur, the transmission routes and the portal of entry in the human host are so far unknown, however. Risk factors remain to be elucidated, but contact to shrews and their excretions should be avoided. 

Thus, as a consequence, BoDV-1 infection has to be routinely considered as differential diagnosis in human encephalitis cases in all regions endemic for animal BD and areas known to harbor BoDV-1 positive shrews.

 

An assumed incubation period of weeks - months may mean that acute BoDV-1 encephalitis could present outside of BD endemic areas as well.

For a list of the group's publications about BoDV-1click here


 

Host switching events were detected as dominant evolutionary mechanisms driving the virus-host associations. Virus spread by animal trade followed by subsequent local micro-evolution in zoos and holdings is responsible for diversifying strains. While zoos had kept predominantly Prevost’s squirrels, private breeders partly had kept variegated squirrels and Prevost’s squirrels in close proximity, resulting in an enhanced probability of cross-species transmission.

Understanding the epidemiology of VSBV-1 spread is crucial to develop and implement surveillance strategies for control. The studies underscore the risk of VSBV-1 transmission in private and occupational settings and the need for monitoring of all exotic squirrel holdings. Examinations of wild exotic squirrel populations and investigations of human encephalitis cases of unknown aetiology for VSBV-1 infection in the tropics may shed more light on the epidemiology and the geographic origin of VSBV-1.

For a list of the group's publications about VSBV-1click here

Epidemiological studies of VSBV-1 introduction and spread

Epidemiological and serological investigations were performed in various German zoos and among squirrel breeders, leading to the discovery of further confirmed, probable, and possible human cases. A complex, intermingling trading network involving several squirrel species, private animal breeders/keepers and zoological gardens was investigated.

The studies provide insight into the spread of this novel viral pathogen among different exotic squirrel species in captivity and spill-over infections to humans.

The striking genetic homogeneity of all currently known VSBV-1 genomes suggests a single introduction of the virus into the known captive exotic squirrel populations in Europe, which is supported by consolidation of phylogenetic analysis and trade network investigations. Phylogenetic data indicate that the initially infected animals in the here identified network were Prevost´s squirrels.

 


Immunological studies of bornavirus encephalitis

Bornaviruses are not cytolytic, and the severe tissue destruction seen during encephalitis by either virus is immunopathgenetically induced.

For BoDV-1, a marked and increasing immune activation during encephalitis is shown in serum and CSF. A pro-inflammatory state as part of the immuno-mediated pathology, shown by elevated respective cytokines, chemokines and other biomarkers, dominates during the course of human BoDV-1 encephalitis. IFNγ production was demonstrated in endothelial cells, astrocytes and microglia, IL-6 in activated microglia, and TGF-β1 in endothelial cells, activated astrocytes and microglia. Pathologically low growth factor levels were seen. This dysbalanced, pro-inflammatory state likely contributes importantly to the fatal outcome of human BoDV-1 encephalitis, and might be a key target for possible treatment attempts in addition to antivirals.

For VSBV-1, and similar to BoDV-1 analyses performed by others, inflammatory infiltrates in areas positive for viral RNA and antigen consist of CD4+ and CD8+ T cells, with perivascular B-cell accumulation. Strong microglial response and bizarre astroglial expansion were present. Hallmarks of apoptosis were seen, such as cleavage of caspase 3 in cells adjacent to CD8+ cells and widespread p53 expression.

For a list of the group's publications about bornavirus immunopathologyclick here

 


RG Zoonoses

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Research Group Leader

Prof. Dr. Dennis Tappe

Telefon: +49 40 285380-499

Fax: +49 40 285380-252

E-Mail: tappe@bnitm.de