A virus that jumps from shrews to humans could have been causing encephalitis unnoticed for decades in regions where the host shrew lives in the wild.
Eight newly-identified fatal cases of Borna disease virus 1 (BoDV-1) suggest that where the virus occurs in the wild, it could be behind a high proportion of severe and deadly cases of encephalitis, according to results from 56 patients who had developed signs of encephalitis over the past 20 years, published in The Lancet Infectious Diseases journal.
Although there is no proven treatment, the researchers behind the new study suggest that clinicians should test for BoDV-1 more often, so that the true extent of infection in humans can be established. The authors suggest testing for its presence in all patients affected by rapidly evolving central or peripheral nervous system disorders where the cause is unknown and where the patient may have come into contact with the infected reservoir host, the bicoloured white-toothed shrew.
All patients in which the virus has been newly diagnosed died between 1999 and 2019, and they all lived in southern Germany. However, the authors cannot rule out that it could be behind milder cases of encephalitis, especially in regions of central Europe where the infected host animal species occur in the wild. It was thought it might play a role in psychiatric disorders, such as depression or schizophrenia, but until the virus was reported in four cases in 2018, its links to unexplained encephalitis were rarely investigated.
BoDV-1-infected bicoloured white-toothed shrews occur in Germany, Austria, Switzerland, and Liechtenstein, but how the disease virus jumps from shrews to humans is unclear. Symptoms in infected people start with a fever, headache and confusion, and continue with signs of brain disease such as an unsteady gait, memory loss, seizures, and a progressive loss of consciousness. In the new cases, symptoms deteriorated rapidly following patients' admission to hospital, leading to deep coma and death. All eight patients died within 16 to 57 days of admission.
"Our tests bring the total number of reported cases of human Borna disease virus in southern Germany to at least 14, so it is still relatively rare in absolute numbers, but it might be behind a larger proportion of unexplained severe to fatal encephalitis cases. Only more tests on patients with severe or even deadly encephalitis will find this out, and earlier detection might be possible using serum and cerebrospinal fluid samples from living patients," says Professor Martin Beer from Friedrich-Loeffler-Institut in Germany. 
For the current study, the researchers analysed brain tissue from dead patients with encephalitis thought to be caused by a virus that had not been identified. The samples were submitted for diagnosis between 1995 and 2018. The authors analysed for genetic signs of Borna disease virus. When sequences of BoDV-1 were detected, they compared them with gene sequences from shrews and from agricultural animals like horses and sheep accidentally infected by the virus.
In 28 patients, the cause of encephalitis was unknown, and nine of these patients died. Six of those who died have been newly diagnosed with BoDV-1 and an additional two cases were independently identified during diagnostics on brain autopsy samples. By contrast, no surviving patients were diagnosed with the virus. However, the scientists note that further research is needed to determine whether it could also be behind milder cases of brain inflammation.
"Our findings indicate that Borna disease virus infection has to be considered a severe and potentially lethal human disease transmitted from a wildlife reservoir. However, it's not a newly-emerging disease, but one that appears to have occurred unnoticed in humans for at least decades, and may have caused other unexplained cases of encephalitis in regions where the virus is endemic in the host shrew populations," says Professor Barbara Schmidt from Regensburg University Hospital, Germany. 
The authors note that a limitation of their study is that they were unable to establish an exact route of transmission from shrews to humans. However, they analysed available information on 14 patients and found that contact with animals, living in rural or suburban areas, agricultural work, and other outdoor activities were reported for most of the patients. In at least seven cases, close contact with cats was reported. When cats hunt, they might bring shrews into their homes, exposing humans to them.
The gene sequences of BoDV-1 in all eight of the new cases were different from each other and matched gene sequences from locally infected shrews or horses, suggesting that infection from the host wildlife reservoir occurred independently each time.
In 2016, three people developed severe or fatal encephalitis from Borna disease virus after receiving organs from the same transplant donor, so the researchers investigated the possibility of this route of transmission for two of the new cases. These two patients received organs from two different donors, followed by immunosuppressive therapy to avoid organ rejection. However, results from the current study argue strongly against the donor organs as a route of transmission. Other recipients of organs from the same donors did not experience any health problems of note, and sequences from the virus in one of the patients closely resembled sequences from infected horses and other infected humans from the same locality.
Writing in a linked Comment, Dr Tomoyuki Honda from Osaka University, Japan, says: "Niller and colleagues' study has several implications for the pathology and epidemiology of Borna virus infection." He continues: "For several decades, the field has been hindered by the controversy surrounding true and false human Borna virus cases. It is time to relaunch human Borna virus research based on a theoretical framework that integrates the knowledge from these confirmed human Borna virus cases."
Peer-reviewed / Experimental study / People
NOTES TO EDITORS
This study was funded by the German Federal Ministry of Education and Research. It was conducted by researchers from the research consortium ZooBoCo (full list at the end of the Article).
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