Research teams on a project to find and predict pathogen emergence have discovered more than 800 novel viruses in wild animals over the past five years.

Dr. Christine Johnson, one of the principal investigators for the U.S. Agency for International Development–funded Emerging Pandemic Threats project Predict at the University of California-Davis, said the effort has provided vast information on viruses, particularly those present in wildlife most likely to spread disease to humans. The hundreds of project workers—who have trained thousands more in disease detection and surveillance—have found potential pathogens such as viruses similar to those that cause severe acute respiratory syndrome and Middle East respiratory syndrome.

A Predict project staff member works on viral detection and discovery at a partner laboratory in Kathmandu, Nepal.(Courtesy of the UC Davis One Health Institute)

Dr. Jonathan H. Epstein, a veterinary epidemiologist for EcoHealth Alliance, a nonprofit public health and conservation organization participating in Predict, said that the project could reduce the risks posed by wildlife-source pathogens.

“We’ve never really known what the collective diversity of viruses is in wildlife, and these are the viruses that jump into people and cause outbreaks like SARS, like MERS, like HIV, and now we have the ability to understand more and more what is out there,” he said. “And so, if there is an outbreak in the future, it’s less likely to catch us by surprise, and we’re actually hoping to just more rapidly be able to identify where these viruses come from if they do get into human populations.”

While Predict’s teams are taking samples largely from healthy wildlife, a separate research group at the UC-Davis School of Veterinary Medicine is looking for viruses in tissues of animals that had clinical signs of disease but were negative for known pathogens. Dr. Patricia A. Pesavento said her group in the Pesavento Research Laboratory, in collaboration with virus hunter Eric Delwart, PhD, and the shelter medicine team at UC-Davis, has found viruses such as a circovirus that could be connected with vasculitis and hemorrhagic gastroenteritis disease in dogs, a polyomavirus connected with brain tumors in raccoons, an astrovirus that causes neurologic disease in cattle, and at least three previously unidentified viruses that circulated among cats in an animal shelter. The team has discovered other viruses in dogs, foxes, and alpacas.

Weekly, if not daily, Dr. Pesavento said, “We’re making decisions about whether or not we should go deeper, if you will, with sequencing or a degenerate primer strategy to try to find what is causing disease in those animals.”

Dr. Delwart, senior investigator for the Blood Systems Research Institute in San Francisco and an adjunct professor of laboratory medicine at UC-San Francisco, said that research on virus detection and characterization in animals is still near its beginning. He hopes the work eventually will lead to better diagnostic tests and even vaccines.

Accelerated discovery

A scientific article, “A strategy to estimate unknown viral diversity in mammals,” published in September 2013 in MBio, the American Society of Microbiology’s online, open-access journal, includes an estimate that mammals are carrying at least 320,000 undiscovered viruses within nine virus families of interest. Finding 85 percent of those viruses would cost about $1.4 billion, and finding nearly all would cost $6.3 billion, the article states.

Dr. Epstein, who co-authored the article, said the rate of virus discovery has accelerated in the past five years as sequencing technology has become more affordable, and more people know how to interpret information from virus studies. EcoHealth is working, in part, to identify viruses that have the potential to emerge from wild reservoirs, particularly rodents, bats, and primates.

Dr. Pesavento said her work depends on time, a strategy for hunting for viruses, and submissions by clinicians who recognize unusual forms of disease.

“The methodology now is so exquisitely fine and financially feasible that we’re finding viruses at a very, very rapid rate,” she said. While she said discovery is important, linking viruses to disease is more important, and it requires more careful study.

Dr. Delwart, whose research has involved evolution of blood-borne viruses such as the HIV virus, recalled reading in 2001 a scientific paper that showed the potential for explosive growth in virus discovery through the deep genetic sequencing process he now uses. While he said people have described his work as a fishing expedition, he characterizes it as fishing with dynamite.

Dr. Delwart said he is particularly interested in viruses from species that have close contact with humans, such as farm animals, pets, and rodents, although he will examine interesting samples from, for example, an exotic bird with strange clinical signs. He even was among authors who wrote in a recent issue of the Proceedings of the National Academy of Sciences about two viruses recovered from 700-year-old caribou feces, one related to viruses that infect plants and fungi and another related to an insect-infecting virus.

Using the results

Dr. Pesavento noted that, even if surveys find most of the viruses circulating in dogs and cats, she doubts samples from every sick pet will be subjected to, say, 150-virus panels, especially since those panels could indicate the presence of viruses that are not causing harm. And she said the ability to find viruses has not been matched by adequate understanding of co-pathogens, particularly combinations that cause disease only when a host responds to stress or environmental factors.

An in situ hybridization image showing bovine astrovirus, in brown, within neurons of a steer’s brainstem (Courtesy of Dr. Patricia A. Pesavento)

If two viruses together cause a problem, researchers have few ways to identify that interaction.

“We’ll find them, but we can find them in normal animals, and so how do we handle that?” she asked.

She described the effort to understand the interaction of viruses and host factors as a new horizon of viral discovery.

Dr. Johnson, who is also a professor of epidemiology in the UC-Davis veterinary school, said the Predict program screens for families of viruses known to cause disease in humans, but those viruses do not necessarily cause disease in their natural hosts. That work and efforts to build capacity for disease detection have taken place in 20 countries in Africa, Asia, and Latin America.

Dr. Epstein said countries’ leaders seem to increasingly see the value of understanding viral diversity in wildlife. Knowing which species carry particular viruses and the routes through which people can become infected can reduce the risk or impact of outbreaks.

He cited the emergence of the Ebola virus as an event in which such knowledge could have been helpful.

“We’d be less likely to be surprised, say, that Ebola exists in wildlife in West Africa and has the potential to emerge,” he said.

Faster identification of pathogens and their animal sources can hasten response, saving lives and resources, Dr. Epstein said. Most of the viruses identified through Predict have long-term associations with host animals that appear to be healthy while carrying the viruses.

”We’re not just interested in looking at what viruses are out there but also in looking at the ecological context,” he said. “And it’s so important to get the message across that most of these viruses we’re discovering seem to be normal microbial flora in wildlife.”

Those animals are not to blame for infections in humans, whose activities such as expanding agriculture, urbanization, and deforestation are drivers of crossover infections. Predict is working to help governments build surveillance capacities and increase their ability to identify zoonotic disease risks.

The USAID has committed to spending up to $100 million on the project over another five years, and Dr. Johnson said the project will become limited to Africa and Asia while expanding sampling activities to additional wildlife and livestock and the people who come into contact with them.

Dr. Dennis Carroll, director of the USAID Emerging Threats Unit, said that, by improving our understanding of the virus families that circulate in animals and that could cause disease in humans, the Predict project can help disrupt disease emergence and reduce the risk of an epidemic in humans. He said the program already has improved understanding of the roles of wildlife, livestock, and human populations in disease emergence.

Dr. Epstein said that, as human activities intensify to meet the growing demand for protein, contact among humans, wildlife, and livestock likely will expand.

“So, we need to be aware of that as a veterinary community and understand that there are real public health consequences to these activities that may go beyond some of the diseases we’re used to thinking about” in livestock and people, he said.

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