March 4, 2015
In Liberia, Sierra Leone and Guinea, doctors and aid workers fight a daily uphill battle to control the largest Ebola outbreak in history. The United States has, apart from four cases, remained untouched.
Yet a small but important battle against Ebola is being fought in Chapel Hill and on its front lines: mice.
Biologists and doctors from UNC Chapel Hill — in collaboration with others from the University of Washington and the National Institute of Allergy and Infectious Diseases — engineered strains of mice susceptible to and resistant to Ebola hemorrhagic fever. This work, published in the journal Science, not only provides a mouse model in which researchers can test future Ebola treatments and vaccines, but also provides valuable genetic information as to why some people are hit harder by Ebola than others.
Ebola hemorrhagic fever, also called Ebola virus disease, is highly infectious and characterized by fevers, pain, blood clotting, bruising and bleeding. As of November 1, the current epidemic had infected more than 13,000 people, killing more than 36% of them. And while an experimental Ebola vaccine, developed by the National Institutes of Health and GlaxoSmithKline, is currently undergoing human trials in Maryland, research is still needed to develop treatments for those who already have the disease and vaccines for different strains of Ebola.
The first stop for experimental drugs is usually in mice, but Ebola does not affect mice the same way it affects humans. Specifically, mice can contract the virus and experience the fevers and pain, but the virus does not cause mice to hemorrhage (bleed and bruise) the way 30-50% of humans do.
This is a major obstacle for researchers, because the hemorrhaging is arguably the most important symptom to stop. Without proof that a treatment can stop hemorrhaging, researchers cannot make a good case that the treatment can effectively save Ebola patients.
In the past, researchers have resorted using monkeys — which GlaxoSmithKline used to test their vaccine — Syrian hamsters, and guinea pigs in animal trials because they can exhibit the hemorrhage symptoms, but mice are much more abundant and easier to work with.
Where normal mice fail, however, is mice from the Collaborative Cross (CC) succeed. The CC mice are a genetic mixture of eight strains of mice commonly used in medical research. The mice are housed at UNC and developed in part by UNC scientists. The genetic diversity allows researchers to see how different genetic traits interact with an invading disease.
When researchers infected 47 genetic lines of CC mice with a strain of Ebola adapted for mice — the researchers found that normal or “wild-type” Ebola could not multiply in mice — they found the mice developed hemorrhaging at a similar rate to humans. Further, they found a group of mice not only survived the infection, but within two weeks had regained the body weight they lost when they were sick, indicating that they were perfectly healthy.
This naturally begged the question of why some mice were able to fully recover while others hemorrhaged and could not. The researchers investigated if there was any difference in how genes were expressed between the resistant and susceptible mice. They found two genes, Tie1 and Tek, were expressed more in the spleens and liver cells of the resistant mice. Tie1 and Tek control the repair and creation of blood vessels.
Next the researchers looked at the genomes of the eight founding fathers (and mothers) of the CC mouse line for differences with regard to Tie1 and Tek. While they were not able to make a significant connection between differences in Tie1 and mouse physiology, differences in the Tek allele were commonly associated with clotting disorders and malfunctioning blood vessels. In the Ebola mice, differences in the Tek allele statistically predicted the onset of Ebola-related weight loss and when and whether the mice would die.
The similarity between the hemorrhage rates of mice and humans in the current outbreak suggests that the symptoms of Ebola may be mediated by our genetics. Whether genetics will play a role in how researchers treat Ebola is a subject for future research. For now, researchers who fight Ebola in the lab have a new weapon in the Collaborative Cross mice.
— Daniel Lane
Daniel Lane covers science, engineering, medicine and the environment in North Carolin