Some people exposed to the Ebola virus succumb to bleeding, organ failure, and shock; others might suffer moderate, maybe even severe illness, but then fully recover. Still, there are those who are completely resistant. Working with genetically diverse mice, researchers show that—like people—the new mouse models do respond to the virus with a huge range of mild-to-deadly outcomes. And importantly, how a mouse responds to the Ebola virus depends on its genetic makeup. The work is published in Science this week.
Conventional lab mice infected with Ebola die, but they don’t replicate the hallmark symptoms of the lethal hemorrhagic fever seen in humans: delayed blood clotting (or coagulation) and death from shock. "You can't look for a cure for Ebola unless you have an animal model that mimics the Ebola virus disease spectra," Ralph Baric of University of North Carolina at Chapel Hill explains in a university statement.
In a biocontainment safety level 4 lab at the National Institutes of Health Rocky Mountain Laboratories in Hamilton, Montana, a large interdisciplinary team tested the effects of Zaire ebolavirus (or EBOV, the same species causing the current 2014 West Africa outbreak) on Collaborative Cross mice. These rodents are a cross of five classic lab strains with three wild-type strains. "They're really more comparable to genetically diverse populations such as humans, but they're reproducible," University of Washington's Angela Rasmussen tells the Los Angeles Times. "We know exactly how one mouse is different to another."
All of the mice lost weight in the first few days after infection, but mice with certain genetic backgrounds were susceptible to the virus while others were resistant. “Genetic factors play a significant role in disease outcome,” Michael Katze of UW says in a news release. "We hope that medical researchers will be able to rapidly apply these findings to candidate therapeutics and vaccines.”
Seventy percent of the mice had a greater than 50 percent mortality. Of them, 19 percent had liver inflammation without classic Ebola symptoms, but 34 percent had blood that took too long to clot. Those mice also had internal bleeding and showed swollen spleens and changes to the color and texture of the livers.
Eleven percent were partially resistant, and over half of these mice survived. And of all the infected crossbred mice in the study, 19 percent were totally unfazed: Not only did they survive, they also fully regained their lost weight within two weeks. A dissection revealed no pathological evidence of disease, and their livers looked fine.
By examining the genomes of these crossbred mice, researchers pinpointed a single gene that likely influences virus susceptibility: the gene responsible for encoding a protein known as TEK, which has been known to activate blood-clotting factors. Additionally, in survivors, there was more activity in genes for blood vessel repair and the production of infection–fighting white blood cells.