How can genetically diverse mice help in the fight against Ebola?
It’s a scary disease. What’s happening in western Africa now is horrific. But I admit I’ve had to tune out from much of the coverage, because most of it isn’t about the virus or the African crisis or the clinical response any more. It’s about what science writers are calling Ebolanoia, the panic that makes people do and say irrational things.*
Perhaps because of this, I skimmed past a Science paper that promised some insight into the genetic underpinnings of variable Ebola pathology in patients, even after it was written up for The New York Times. But it came across my radar again, and I stopped to take a closer look.
It turns out the mouse models previously used to study Ebola—or, rather, a mouse-adapted strain of Ebola—were not very good. The disease is lethal in mice, but the symptoms observed in the models were quite different from those of humans. As a result, other mammalian models have been used, but they are far less available, more expensive and difficult to work with than mice. Added to the obvious overhead already involved with Ebola virus research, which requires the strictest biosecurity measures available, and it’s easy to see why little progress has been made into learning about Ebola’s basic biology. (For an excellent overview of what is known, see this recent article in Nature News.)
Nonetheless, researchers at the University of Washington were able to use mice to address an important question: why is the pathology of Ebola different in different people, so while a high percentage die, a smaller percentage not only survive but do so with no lingering aftereffects? To answer this, they turned to the Collaborative Cross (CC), a panel of mice generated from eight founder strains that allow researchers to capture wide genetic diversity while still providing precise inbred genotyping. JAX has been at the center of the effort to develop CC mice and promote their use.
I previously discussed the CC and how it can overcome the limitations of preclinical research done using a single inbred mouse strain. And the CC panel worked beautifully for investigating differing pathogen response. Different CC mice displayed a range of disease progressions, from resistance to lethality, in ways that closely resemble the human response. The mechanisms behind the different responses were related to inflammatory/immune pathways, as has been observed in human patients. And by comparing the genetics of the mice that displayed variable responses, the researchers were able to identify genetic differences underlying susceptibility, particularly as it related to cellular adhesion and resistance to hemorrhagic bleeding.
This paper is just a start, but the insights provided by working with the CC mouse population already represent a huge boost to the Ebola research effort. Better understanding of the genetics of resistance has provided therapeutic targets to investigate. And having mice available that provide good models for Ebola infection in humans will greatly accelerate the development of working treatments for the disease.
The unknown and incurable are frightening. The more we know, the better our response will be. And if an effective therapy can be developed, it will ultimately provide a cure for Ebolanoia as well.
*For example, I live in the same state as Kaci Hickox, the nurse who is being quarantined simply because she worked with Ebola patients. She doesn’t have any symptoms or indication at all that she has the disease. Nonetheless, I’ve seen firsthand the nonsensical fear her mere presence in the state has provoked in people who live hundreds of miles away from her home in Fort Kent. And it is the fear that concerns me far, far more than Ms. Hickox or any person who has worked with Ebola patients, whether they live next door or on the other side of the continent.