New research into the effects of the Ebola virus on mice indicates that individual genetic differences may play a key role in determining the severity of the illness and, ultimately, the likelihood of surviving it.
The experiment — the first of its kind — could indicate that genetics play a similar role in humans, say the researchers, who published their findings this week in the journal Science. If scientists can pinpoint the exact genes that allow some human Ebola patients to avoid the worst symptoms of Ebola, such as hemorrhaging, it could help speed up the development of potential vaccines against the virus.
“This [experiment] will ultimately allow us to not only better understand what predisposes an individual with a particular genetic background to either susceptibility or resistance [to Ebola], it will also provide a genetically diverse yet reproducible model in which to test drugs and vaccine,” Dr. Angela Rasmussen of the University of Washington and a lead researcher on the study, told Forbes.
Dr. Rasmussen’s team identified two genes in mice that controlled for resistance to the worst symptoms of the disease. Both genes produce the proteins TIE1 and TEK, which help regulate how much fluid passes through the walls of the body’s blood vessels. These genes were less active in mice that experienced hemorrhaging — a symptom that produces the bloody eyes, gums, vomit and diarrhea witnessed in about a third of human Ebola patients.
New mouse model replicates human immune response to Ebola
Scientists have long known that Ebola affects people differently, but the reasons for this variation are not fully understood. “All we know is that not everyone gets hemorrhagic fever, not everyone gets sick,” Michael G. Katze of the University of Washington, who, along with Rasmussen, started experimenting with mice and Ebola three years ago, told the New York Times. “There are a million articles about Ebola but very little scientific literature on the virus.”
Some people are thought to be completely resistant to the Ebola virus. Others suffer moderate symptoms such as fever, and still others become seriously ill. Hemorrhagic symptoms occur in about 30 percent to 50 percent of patients, according to an October report in the New England Journal of Medicine. Natural resistance to the Ebola virus is critical to a patient’s likelihood of survival, researchers have said.
In this latest study, Dr. Rasmussen and colleagues from the National Institutes of Health’s (NIH) Rocky Mountain Laboratories in Montana and the University of North Carolina at Chapel Hill developed a novel mouse model to study the immunological response to Ebola. Until now, monkeys were considered the best animal models for Ebola, as they have similar immune responses to humans. But monkeys are also expensive to keep and much more difficult (and more dangerous) to work with than smaller animals like rodents. However, since traditional lab mice die from Ebola without ever developing symptoms, scientists have been left with very few options for animal models.
Dr. Rasmussen’s team circumvented those obstacles by using a group of mice that were bred to have high genetic diversity, as opposed to the typical laboratory mice, which are produced by many generations of inbreeding and are therefore extremely similar. While most lab mice only represent about 10 percent of the genes in the total mouse population, this group of mice cover 90 percent of the species’ genetic diversity.
When infected with the virus, the genetically diverse mice exhibited a full range of Ebola symptoms: some mice were resistant to infection, some showed symptoms but survived, and some were similar to classical lab mice (they died without showing bleeding symptoms). About 40 percent of the animals developed blood and liver problems similar to the hemorrhagic disease that is seen in some Ebola patients, the researchers said.
The findings suggest that “the genetic background of the individual who is infected plays a really significant role in determining how serious their Ebola virus disease is going to be,” said co-author Angela Rasmussen, a virologist at the University of Washington.
Findings could inform more effective drug development
Experimental Ebola drugs like Zmapp contain antibodies against the virus and work by boosting immunity. The virus must ultimately be defeated by the body’s immune system, but buying the body more time to develop antibodies could mean the difference between life and death. An Ebola vaccine that targets the genes that control for hemorrhaging could give patients who do not have a natural resistance to the virus a fighting chance.
The study is “the first step in being able to do this kind of genetic analysis in humans,” Katze told the Washington Post. “You can go to the doctor and get your genome sequenced and find out how likely you are to get certain types of cancer. Maybe someday they’ll also say, ‘Hey, don’t go to West Africa, it looks like you’re susceptible to Ebola.’”
More than 13,700 cases of Ebola and nearly 5,000 deaths have been confirmed in the 2014 outbreak, the largest in history and the first to reach countries outside of Africa. The epidemic, which the World Health Organization (WHO) recently called the “most severe acute public health emergency in modern times,” has created unprecedented demand for drugs to treat and prevent the feared virus. In addition to testing several new experimental drugs and vaccines, scientists also recently announced plans to start trials assessing the effectiveness of convalescent serum — blood products obtained from Ebola survivors — as a treatment for the disease.
The rationale behind this approach is that blood from recovered patients contains antibodies and other components that may help the transfused patient fight off the virus. Antibodies are produced by the body’s immune system to fend off harmful things such as viruses. They remain in the blood ready to fight off any future infections by the same foreign substance. Blood from survivors of diseases including bird flu and anthrax has been used in the past when doctors ran out of options and seems to work best in diseases where there’s a toxin, such as anthrax and tetanus.
In this current outbreak, perhaps the most famous donor of “convalescent serum” is Dr. Kent Brantly. When he was diagnosed with the disease in Liberia, he received a blood transfusion from a young teen who had survived Ebola with Dr. Brantly’s help. Since returning to the U.S., Dr. Brantly has donated his blood to American missionary doctor Rick Sacra, NBC cameraman Ashoka Mukpo and Dallas nurse Nina Pham, all of whom had matching blood types to Dr. Brantly. Most recently, American Ebola survivor Nancy Writebol, who contracted the virus while working as a missionary in Liberia, donated her blood to Amber Vinson, the second Dallas nurse infected with Ebola.
At this point, all of the Americans who received transfusions of survivors’ blood have been declared Ebola-free. However, it is not possible to determine whether the convalescent serum had any effect on their recovery, as they all also received intensive medical care and supportive therapy, which confound any potential effects of the treatment. Scientists hope to start testing the procedure in a more controlled setting by the end of the year.
The goal is to recruit at least 200 patients to receive either whole blood or blood plasma from an Ebola survivor. Their outcomes will then be compared with a greater number of patients who don’t receive transfusions because they don’t have matching donors. All patients will receive a standardized level of supportive care, including intravenous fluids. If effective, convalescent serum could be scaled up quickly as a short-term intervention while work continues to develop drugs and vaccine for the deadly disease.