Virus Spread by Shrews Linked to Human Deaths from Mysterious Brain Infections
Borna disease virus 1 (BoDV-1) causes a bizarre and deadly neurological infection in horses, sheep and other domesticated mammals in parts of Germany, Switzerland, Liechtenstein and Austria. Borna disease was named after a city in eastern Germany where it once killed numerous horses in the late 19th century. Infected animals have been known to engage in strange behaviors, such as smashing their heads into things, as well as “pipe smoking”—an informal term for when animals are eating hay and suddenly stop chewing mid-mouthful, with the uneaten portion protruding like a pipe. But the disease does not appear to spread between horses; they are thought to acquire it from shrews, which can live in hay and secrete or excrete fluids containing the virus.
About 14 years ago, researchers identified the bicolored white-toothed shrew as a reservoir host—an organism in which a virus replicates but does not usually cause illness—for BoDV-1. Horses and sheep are considered “dead-end hosts” that cannot spread the pathogen. For decades, scientists had debated whether the virus is zoonotic, or capable of jumping from animals to humans. Several studies even suggested that it might be present in people with psychiatric disorders such as depression, schizophrenia and bipolar disorder. It was later shown, however, that the viral RNA sequences detected in these studies were likely the result of laboratory contamination, and research on human infections subsided.
But in 2015 a related type of bornavirus found in exotic squirrels was implicated in at least four human deaths. Then, between 2018 and 2019, scientists detected the classical bornavirus, BoDV-1, in five people in Germany who suffered serious or fatal encephalitis (brain inflammation caused by infection)—three of whom were recipients of organ transplants and were taking drugs to suppress their immune system. Now, in a study published Tuesday in Lancet Infectious Diseases, researchers have reported eight additional cases of BoDV-1 infection in humans who died of encephalitis. The pathogen appears to have flown under the radar for decades, but the researchers say doctors should be considering it a potential cause in such deaths.
“We now have eight more cases, and these provide additional material for a better understanding of the disease,” says Martin Beer, head of the Institute of Diagnostic Virology at the Friedrich Loeffler Institute in Germany, who was co-senior author of the new study and was also part of the team that reported the squirrel bornavirus infections. The findings confirm that the virus can infect humans and cause deadly encephalitis. “But the risk is, to our opinion, pretty low,” Beer says.
Beer and his colleagues analyzed postmortem brain tissue from 56 patients in southeastern Germany’s state of Bavaria between 1999 and 2019. The samples were tested for genetic material from BoDV-1, which the researchers verified by additional testing for antibodies to it. Seven out of nine patients who died of encephalitis of unknown cause at one diagnostic center later tested positive for the virus (one of these cases had been reported previously). An additional two cases that tested positive were also included in the analysis.
The results confirm the virus had caused eight new encephalitis cases; two of these were immune-compromised individuals who had received organ transplants, and six were not. Because other recipients of organs from the same donor did not test positive for the virus, researchers think the transplant recipients that died from the virus probably acquired it from being immune-compromised, not from the donor. The patients suffered symptoms including headache, fever and confusion, which later progressed to coma and ultimately death.
All of the patients lived in rural areas and worked or spent a lot of time outside. Most had also been around cats, which are known to catch shrews and sometimes present them to their owners. Beer and his team hypothesize that the patients were exposed to BoDV-1 this way or perhaps by inhaling dust containing dried shrew urine. Future research will be needed to determine the exact infection route, he says.
Once in a human or horse host, the virus is thought to cross the blood-brain barrier into the central nervous system, where it triggers the host’s immune system to attack brain tissue. “It’s not the virus killing the brain cell or nerve tissue,” Beer explains. “It’s the [host’s] own immune system recognizing the infection and starting to kill parts of brain.”
There is no known treatment for the disease, but researchers are exploring whether antivirals such as ribavirin—which has been shown to kill a range of bornaviruses in cells grown in a dish and in animal studies—could be effective in treating BoDV-1 infections in humans. Beer and his colleagues have plans to test newer antivirals against the virus in animal studies.
“I think it’s an excellent paper,” says Norbert Nowotny, a professor of virology at the University of Veterinary Medicine, Vienna, who was not involved in the new study but was part of the group that discovered shrews were a reservoir host for the virus. “This Borna disease is really a strange disease—it’s not like a flu,” he adds, noting that it does not cause epidemics. “It’s a single-animal disease, and it seems to be the same in humans.”
The virus itself is somewhat unusual in that it has a very short genome and makes only a few proteins. It does not seem to infect many individuals—but when it does, it kills them very efficiently. Numerous other zoonotic viruses infect many people but are seldom deadly. Previous research has found that humans and most mammals actually have bornavirus sequences in their genomes, which may help organisms protect themselves against infection, some hypothesize.
Fortunately, the virus does not appear to be transmitted between humans. “I think we are all happy that this is not a virus that can spread easily,” Beer says. But in light of these new findings, doctors should consider BoDV-1 as a possible cause of encephalitis in areas where it has been known to infect humans and horses.
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