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<i>Science</i>: Genetically Diverse Mice Respond Differently to Ebola Infection

Genetics appears to play a significant role in determining disease outcome when it comes to Ebola, say researchers studying the disease in mice.

Angela Rasmussen and Michael Katze from the University of Washington in Seattle, working with colleagues from across the United States, have discovered that Collaborative Cross mice — a specific strain of laboratory mice that was engineered to be genetically diverse — respond to Ebola virus with a wide range of symptoms.

The Collaborative Cross mice show a variety of responses to Ebola, making them useful in tests of human vaccines for the disease. | Brian Donohue, UW Medicine Strategic Marketing & Communications

Until now, no mouse model of the virus has reproduced the hallmark symptoms of Ebola hemorrhagic fever, such as delayed blood coagulation, internal hemorrhaging, and coffee-colored blood. But Collaborative Cross mice respond to the virus in many different ways, from complete resistance to lethal infection, just like humans do, according to the researchers.

"These mice were all infected by the same virus via the exact same route," said Katze. "The only difference was the genetic background of the mice, so we think that this represents definitive proof that host genetics influences Ebola infection."

"The results give us some clues as to what determines susceptibility to Ebola, and why people experience such diverse responses to the virus," added Katze. "But studies to identify specific resistance and susceptibility genes are more complicated. This is just a first step."

Traditionally, studies of Ebola have been limited to macaques, guinea pigs, and hamsters, which present both practical and ethical concerns. But these researchers hope that Collaborative Cross mice could provide a useful tool for screening candidate therapeutics and vaccines to help combat the virus in the future. Their goal is to eventually develop countermeasures similar to those that are currently available for influenza viruses.

The researchers' findings appear in the 30 October issue of Science Express.

Working under stringent biosafety conditions as part of the team led by Rasmussen and Katze, Atsu Okumura at the Rocky Mountain Labs (a National Institutes of Health facility in Hamilton, Montana) tested the effects of a mouse-adapted strain of Zaire ebolavirus. The researchers did not alter the virus, which is extremely similar to the Ebola strain that caused the current West Africa outbreak, in any way.

They found that the rodents' response mimics that of humans to Ebola, and they suggest that certain genetic backgrounds are susceptible to the virus while others are nearly or completely resistant. One allele in particular known as Tek, which controls blood vessel integrity in healthy mice, may strongly influence the susceptibility of the Collaborative Cross mice to lethal disease, according to the researchers.

"A similar number of humans appear to be resistant to the virus, and they are analogous to the resistant mice in our population," said Rasmussen. "In the past, it's been difficult to show that individual immune responses were not responsible for differences in disease susceptibility. But here we highlight a genetic influence pretty definitively."

Currently, Collaborative Cross mice are the focus of studies around the world aimed at gauging responses to a variety of infectious and non-infectious diseases — and these researchers suggest that the genetically engineered mice will be featured in the news again soon.