Study Suggests Genetics

Genes Influence How Mice React to Ebola, Study Says In ‘Significant Advance’

OCTOBER 30, 2014
Some people exposed to the Ebola virus quickly sicken and die. Others become gravely ill but recover, while still others only react mildly or are thought to be resistant to the virus. Now researchers working with mice have found that these laboratory animals, too, can have a range of responses to Ebola, and that in mice, the responses are determined by differences in genes.

This is the first time scientists have been able to breed mice that developed Ebola infections resembling those in humans complete with some puzzling features seen in people.

About two-thirds of people who die from Ebola never develop the terrifying hemorrhages that appear in others a day or two before death, in which eyes turn fiery red, gums bleed, red dots emerge on the skin as blood seeps out of capillaries, and blood appears in vomit and diarrhea. Many mice, too, die of Ebola without hemorrhages.

The mouse studies indicate the animals that hemorrhage and — by implication, humans— die because their immune systems overreact to the virus. The result is an inflammatory response that makes cells leak fluids and white blood cells, and makes tissues and organs deteriorate. Many die at that point. In those mice — or humans — that survive long enough, the researchers propose, blood eventually starts to seep out of vessels.

Video | Researchers Discuss Ebola Tests in MiceResearchers at the University of Washington have been studying the Ebola virus in mice, and have found that the effects of the virus may be determined by genes.
Although the investigators have not yet pinned down the exact genetic reasons that mice vary so much in their responses to the Ebola virus, they have identified two genes that seem to be crucial in determining if a mouse will die or whether the infected mouse will even become ill.

The study, published online Thursday by the journal Science, is “a significant advance,” said Dr. James Musser, director of the Center for Molecular and Translational Human Infectious Diseases Research at Houston Methodist Research Institute. Using mice in experiments, he said, can change the nature of Ebola research. Until now, investigators have mostly used macaques, guinea pigs, and Syrian hamsters because the mouse strain they usually study does not get an Ebola infection that mimics how human patients react.

“This provides a tremendous opportunity to drive toward answers to questions that heretofore were intractable,” Dr. Musser said, mentioning in particular the question of how much genetics determines susceptibility or resistance to Ebola. He added that the mice could be invaluable in initial tests of vaccines and potential drugs.

Dr. Matthew Waldor, an infectious disease researcher at Brigham and Women’s Hospital who also was not involved with the study, had the same opinion, calling it “a cool study.”


The work, by Angela L. Rasmussen and Michael G. Katze of the University of Washington and their colleagues, began three years ago, long before the current Ebola epidemic. They were inspired by their studies with the 1918 influenza virus that caused a worldwide lethal pandemic.

Using a variety of mouse strains, they found that genetics determined whether a mouse got sick or died from the flu, or never got sick at all. People, too, seem to have different responses to the same influenza virus. Dr. Katze, who has studied Ebola for the past decade, and Dr. Rasmussen, who chose to study infectious diseases because when she was in college she read “The Hot Zone,” a book that told a terrifying tale of Ebola in Africa, wanted to find out if genes determine responses to Ebola.

So little was — and is — known about the disease, Dr. Katze said. “All we know is that not everyone gets hemorrhagic fever, not everyone gets sick,” he said. “There are a million articles about Ebola but very little scientific literature on the virus,” he added, explaining that most of what has been published is opinion pieces, epidemiology, and clinical observations.

He and Dr. Rasmussen decided to study Ebola not just in the one standard mouse strain that had proved so unsuitable for research on the disease but in 47 different genetic varieties. The mice were developed by a consortium of researchers that bred laboratory mice to resemble the genetic diversity found naturally in mice.

But studying Ebola was not easy. The infected mice had to be observed and necropsied in a secure biocontainment lab run by the federal government in Hamilton, Mont.

The first question that intrigued Dr. Rasmussen was, Why do some mice, and humans, die from Ebola?

The mouse studies showed that animals that died after bleeding had an overblown inflammatory response to the virus. They also had low activity of two genes, Tie1 and Tek, that made their blood vessels more permeable. The leaky vessels allowed white blood cells to stream out, escalating the inflammatory response and causing a chain reaction of damaging immune system chemicals that destroyed organs. The same sort of thing happened in mice that died from the flu, although those genes, Tie1 and Tek, did not appear to be involved in the influenza deaths, Dr. Rasmussen said.

She said that “a big take-home lesson from the paper” is that genetics plays a major role in determining the outcome of a mouse’s Ebola infection. By inference, she said, genetics probably plays the same role in humans.

But many questions remain and, even with mice, the work is slow and difficult. There are only about a half a dozen labs in the United States equipped to safely study Ebola, and work in those labs is tedious with researchers dressed in moon suits. It takes years of training to even be prepared to work in one of the labs, Dr. Katze said.

The scientists want to further investigate genes that determine susceptibility in mice and hope to examine tissue from Ebola patients to see if they have analogous genetic variants. But that is difficult, Dr. Katze said. Many labs want tissue samples and, with patients in West Africa, it can be difficult to get an accurate description of the course of the disease. Then there is the question of how to transport the tissue to the United States. “Nobody will let you put it in a can and take it on a plane with you,” Dr. Rasmussen said.

There are now Ebola patients in the United States but because of privacy issues, Dr. Rasmussen said, “the status of tissue or blood samples from those patients is unclear."

For now, said Dr. Katze, the field is somewhat chaotic. “We don’t know what the genes are in humans,” he said, " but when we find out what the genes are in mice, then we have a clue.”

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It is an interesting experiment. To me it may mean the answer lies in gene therapy. What genes those are, and more importantly why, who knows as yet. This study is not to be confused with racial genes, per se, as the variances appear to be within the African people. But we may find out that Eskimos are not much effected by Ebola while redheads have almost a 100% CFR. Who knows as yet. But primarily I think the focus is on differances within any given racial group which there are many as my own Family Tree DNA shows. It is a very important study worthy of further research and noting here regardless of it touching on any geo, hence racial or semi-racial differances.