In a highly secure, ultra-modern biocontainment safety level 4 lab in Hamilton, MT, scientists working with Ebola-infected mice have discovered that host genes may play an important role in deciding whether the virus infection is fatal or not. Their findings suggest in some people, because of their genes, the virus sparks reactions that help to limit the damage of the infection.
Reporting in the journal Science, the team hopes the new strains of mice, which they have developed to study how host genes react to Ebola in the lab, will speed up drug and vaccine development.
Three research centers collaborated on the project: the University of Washington in Seattle, the National Institutes of Health’s (NIH) Rocky Mountain Laboratories in Montana and the University of North Carolina at Chapel Hill.
Earlier studies of people infected with Ebola have found that the diversity of reactions is not necessarily due to the virus itself but factors in the host: some completely resist the infection, others have a mild to moderate reaction, while those who are most susceptible succumb to bleeding, organ failure and shock.
But what was missing in order to explore what might explain this diversity of responses was a reliable animal model that could be used in a safe and secure lab. The researchers behind the new study showed that the strains of mice they have developed meet this need.
They took a genetically diverse group of inbred mice that had been developed to study genes involved in influenza severity and used them to breed strains that replicate the main features of human Ebola hemorrhagic fever.
In the NIH lab in Montana – which complies with federal, state, and local safety and biosecurity regulations – they studied mice infected with a mouse version of the Ebola strains that are currently infecting humans in the 2014 West Africa epidemic.
They found that while all the mice lost weight in the first few days of infection, 19% of them were not severely affected by the virus – not only did they survive, they put their weight back on within 2 weeks. They showed no serious physical signs of disease; their livers looked normal, note the authors.
Meanwhile, another 11% of the mice showed partial resistance to Ebola – less than half of this group died – and the remaining 70% showed severe reactions – over half of them died.
Of the 70% of mice that had a severe reaction, 19% had liver inflammation without classic symptoms of Ebola, while 34% had blood that took a long time to clot – a classic hallmark of fatal Ebola hemorrhagic fever in humans. These mice also showed signs of internal bleeding, swollen spleens and their livers changed color and texture.
When they looked at the various genetic make ups of these groups of mice, the team found the severity of the Ebola infection and rates of death seemed to line up with specific gene patterns.
Their results showed that in general, in the mice that suffered serious reactions and died, the Ebola virus tended to activate genes involved in promoting blood vessel inflammation and cell death. But in mice that survived Ebola infection, the virus tended to activate genes that control blood vessel repair and production of immune cells that fight infection.
The team also noted there could be something happening in the livers of Ebola-resistant mice to reduce disease severity. Some specialized liver cells may have limited virus replication and so minimized severity of systemic inflammation and damage to blood clotting processes.
This could explain why susceptible mice suffered widespread liver infection, their bodies having more of the virus and poor blood coagulation.
They also found that the spleens of the resistant mice took a different route to try and ward off infection than the spleens of susceptible mice.
Lead author Dr. Angela Rasmussen, of the University of Washington (UW) microbiology and systems biology lab, says the frequency patterns of different disease symptoms they saw in the mice are similar to those observed in humans in the 2014 West Africa outbreak.
Senior author Michael Katze, professor of microbiology, and head of the UW lab, says while there may be other reasons to explain immunity in recent Ebola survivors:
“Our data suggest that genetic factors play a significant role in disease outcome. We hope that medical researchers will be able to rapidly apply these findings to candidate therapeutics and vaccines.”
In a letter recently published in the Lancet, some experts raise the possibility that as it rages in West Africa, leaving many deaths in its wake, Ebola could also quietly be immunizing many people. Finding a reliable way to identify them, and perhaps recruit them to help with disease control, could reduce risk of infection to those who are not immune.