Andrew Bennett, a former graduate student in the lab of Tony Goldberg, UW-Madison Professor of Epidemiology in the School of Veterinary Medicine, holds a cyclops leaf-nosed bat during field work in Uganda's Kibale National Park, in search of viruses carried by the animals. Bennett was part of an international team that just described the first two relatives of rubella virus ever found. [Emily Julka]

Scientists working independently across continents have identified the first two relatives of the virus that causes rubella—also known as German measles—a disease that can result in miscarriage, stillbirth, and severe congenital birth defects, when contracted by the mother during the first three months of pregnancy.

Rubella was first described in 1814, and the causative rubella virus (RuV), was first isolated in 1962, but has remained the only known member of its designated riboviriad family, Matonaviridae. Until now, that is, with the identification of two distinct, but related viruses in both wild and captive animals as far distant as Africa and Germany. One of the viruses, given the name ruhugu virus, was found in oral swabs taken from apparently healthy wild cyclops leaf-nosed bats in Kibale National Park, Uganda, and the other, rustrela virus, was identified in an acutely ill donkey, capybara, and Bennett’s tree-kangaroo, at a zoo in Germany, as well as in apparently healthy wild mice near the German zoo.

The two scientific teams made their discoveries independently, and without knowledge of each other, but have now collaborated to describe the new viruses, and outline their respective viral similarities and differences to the human rubella virus. Reporting on their findings in Nature, the scientists suggest that the rubella virus that infects humans may have emerged as a zoonotic infection that jumped from animals. The researchers are now working to further study both viruses in the lab, but point out that neither the ruhugu or rustrela virus is known to infect people.

“There is no evidence that ruhugu virus or rustrela virus can infect people, yet if they could, it might be so consequential that we should consider the possibility,” said Tony Goldberg, PhD, a University of Wisconsin-Madison professor of epidemiology at the School of Veterinary Medicine, who led the U.S. research effort. “We know that in Germany, rustrela virus jumped among species that are not at all closely related. If either of these viruses turns out to be zoonotic, or if rubella virus can go back into animals, that would be a game changer for rubella eradication.”

Goldberg and colleagues in the U.S., and in Germany, report on their combined findings in a paper titled “Relatives of rubella virus in diverse mammals.”

Rubella, which was first described nearly 200 years ago, is an airborne, highly contagious human infectious disease that is typically characterized by a rash, low-grade fever, adenopathy and conjunctivitis, the authors wrote. But while safe and effective RuV vaccines are now used worldwide and have significantly reduced the global incidence of rubella, pockets of the disease do still exist, and about 100,000 cases of the potentially deadly congenital rubella syndrome occur annually. To date, little has been known about how the virus first emerged. “Since 1814, when rubella was first described, the origins of the disease and its causative agent, rubella virus (Matonaviridae:Rubivirus), have remained unclear,” they commented.

Identification of the first two rubella virus relatives is the result of two, independent scientific efforts. One involved a team of American and African scientists, working at night to take oral swabs from insect-eating cyclops leaf-nosed bats in a Ugandan forest. The other started in a necropsy room near the Baltic sea, where scientists were trying to determine what killed a donkey, a Bennett’s tree-kangaroo and a capybara at a German zoo. All of the animals had been suffering from severe brain swelling.

Neither research team was aware of the other, yet they were both—within just months of each other—ultimately to make discoveries that have helped to shed some light on the long-enduring mystery of the rubella virus. “Why has it been so challenging to track down the origins or relatives of rubella virus?” asked Goldberg. “Why did it take 206 years from the time George Maton first described rubella, and why did two teams working independently figure it out within three months of each other, get lucky enough to learn of one another’s results, and then lucky enough to work together to publish?”

It isn’t because people haven’t tried, Goldberg noted. It may be that advancing technology has made it easier. Rubella virus genomes are notoriously difficult to work with, and the new viruses share these characteristics. Alternatively, it may just be serendipity.

Goldberg’s team, whose efforts in the new study were led by former graduate student Andrew Bennett, wasn’t originally looking for rubella-like viruses. The investigators were, pre-COVID-19 pandemic, working with their Ugandan colleagues to look for coronaviruses carried by bats. A sequence leading to identification of the ruhugu virus popped up as they were carrying out their analyses of genetic code from the samples collected.

When they looked more closely, they saw that the new sequence was quite similar to rubella virus, harboring just one amino acid difference in a key region of the genome that lets viruses bind to host cells. They named the virus ruhugu virus (RuhV), for the place where it was found, Ruteete Subcounty, and the word in the local Tooro language that describes the flapping of bat wings in the hollow of a tree: obuhuguhugu. “RuhV was found in 10 out of 20 oral swabs from apparently healthy cyclops leaf-nosed bats (Hipposideridae: Hipposideros cyclops Temminck, 1853) in Kibale National Park, Uganda,” they wrote. “Whether RuhV can infect animals other than cyclops leaf-nosed bats remains unknown.”

The virus found in Germany, which is slightly different again from rubella and ruhugu, was named rustrela (RusV), for the nearby Strela Sound. Rustrela virus has a few more amino acid differences when compared with rubella, and was found in the encephalitic animals at the German zoo. “RusV was found in brain tissues of three acutely ill animals at a zoo in Germany, all of which succumbed to severe, acute neurological disease,” the teams noted. The virus was also found in the brain tissue of eight out of 16 wild yellow-necked field mice both at and near the zoo, although these animals didn’t display any evidence of encephalitis. “The detection of viral RNA in samples from yellow-necked field mice collected between 2009 and 2020 and the absence of inflammation in the mice suggest that this broadly distributed rodent is the reservoir host of RusV,” the team noted.

Rubella has not been found in animals, which has made it easier for the World Health Organization to target elimination of the virus. However, both of the new viruses have been found in common mammal species in Uganda and in Germany, with up to half of the bats and half of the mice tested being found to carry their respective viruses. This suggests that these species may act as their respective viral reservoirs, carrying and transmitting pathogens without getting sick.

The newly reported study also indicates that rubella, like many other human viruses, probably originated in animals, but its now known whether rubella virus can jump back into animals. The team’s analysis suggests the three viruses may be similar enough that the current rubella vaccine could be effective against all of them—a key question for research going forward, said Goldberg, who is also a member of the UW-Madison Global Health Institute.

The new viruses also provide scientists with new tools to probe the biology of rubella virus and the Matonaviridae family. There are currently no good animal models for rubella, but rustrela virus could provide a new opportunity for study, given the widespread use of mice as a model species in the laboratory. “ … our findings will facilitate comparative studies of RuV that were previously not possible, including the potential development of animal models of rubella and congenital rubella syndrome,” the scientists suggested.

They further pointed out that it would be useful to evaluate whether existing serological tests for RuV infection will work in animals, and to develop new assays that can detect and differentiation among rubella-like viral infections in animals and in humans. And while the implication that RuhV or RusV are zoonotic agents is currently speculative, the team noted, “… bats and rodents possess biological attributes that predispose them to hosting many zoonotic viruses, so this scenario should not be dismissed.”

The discovery that RusV can infect both placental and marsupial mammals, and cause disease symptoms that are similar to those of the severe encephalitic forms of rubella in humans, “… reinforces such a precautionary stance,” they stated. “… the ability of RusV to infect mammals across wide taxonomic distances and to cause severe encephalitis in spill-over hosts raises concern about the potential for zoonotic transmission of RuhV, RusV or other RuV-like viruses.”

The study findings additionally reinforce the critical importance of conservation efforts in Uganda to protect forests from encroaching development, and the key work that scientists and others there are undertaking to study the effects of a changing environment on human and animal diseases. For example, the deputy director of field operations for the Uganda Wildlife Authority, Charles Tumwesigye, says that the study’s findings will be incorporated into UWA’s community conservation awareness programs, especially around Kibale National Park, where the ruhugu virus was found.

The study “will help management to further protect unique aspects of the ecosystem as well as keep the population safe,” he stated. “Uganda Wildlife Authority values scientific research because it provides key information for decision-making in protected area management.” Tumwesigye added that the ways in which people and wildlife relate are “key to harmonious co-existence … When communities around Kibale National Park appreciate the value of the bats, for example, they become supportive in their conservation initiatives and learn how to protect themselves.”

And if it were not for the country’s “long history of excellent medical and conservation science,” said Goldberg, “there might have been no bats to study.” Protecting habitat is of utmost importance to animals and to people, he added. “Viruses stay in their place when ecosystems are intact.”

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