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How the Ebola Virus Jams Immune System Signals and Kills

For the first time researchers map out the proteins involved in Ebola's anti-human arsenal.
August 31, 2014, 10:00am
Image: the Ebola virus/CDC/Cynthia Goldsmith

The largest Ebola outbreak in history has been making headlines for months. Health officials and government leaders from West Africa and well beyond have been left perpetually scrambling to get ahead of a disease still boasting a mortality rate near 50 percent. The current confirmed death toll: 1,552.

Researchers based at Washington University School of Medicine, however, have figured out how Ebola manages to be so uniquely deadly in humans, by mapping out in detail how one Ebola virus protein interacts with a protein integral to human immune systems. This is good news because deep knowledge of the ins and outs and intricacies of Ebola makes finding a cure and vaccine for the virus all that much easier.


Scientists have known for a while that this one particular Ebola protein was messing with our human one, but were unsure of these exact specifics, published this month in the open-access journal Cell Host & Microbe.

The Ebola virus protein in question is called VP24. When Ebola enters an organism, VP24 binds to a protein in the human host known as the KPNA5. The KPNA5's job is one of communication between cells, which it does by taking signals into and out of a cell nucleus, like a messenger or bus. Proteins like KPNA5 carry all sorts of signals, or messages, to and from the nucleus to other parts of the cell. These messages regulate various functions in an organism, including its immune response.

It's like the VP24 is taking STAT1's seat on the bus to the nucleus.

When the Ebola protein VP24 latches onto its messenger protein target, that messenger protein becomes unable to carry an important immune signaling protein called STAT1. The VP24 binds itself to the same place the human STAT1 protein would, so it's like the VP24 is taking STAT1's seat on the bus to the nucleus.

"Normally STAT1 is transported into the nucleus and activates the genes for hundreds of proteins involved in antiviral responses," said co-author Daisy Leung, an assistant professor of pathology and immunology at WU, in a press release. "But when VP24 is attached to some of these transporters, STAT1 can't get into the nucleus."


Or, as the paper describes it: "inhibition of PY-STAT1 nuclear localization by eVP24 is due to direct competition by eVP24 for NPI-1 subfamily KPNA binding."

Graphical abstract from the paper

Normally, when a nucleus receives the STAT1 protein, it sounds the cellular alarm and releases interferons (think "interfere") which then fight the virus, bacteria, or whatever other pathogen is attacking the cells. However, since Ebola has prevented the cell's call-to-arms for interferons from even happening, the immune system is delayed and when it finally arrives, it's already overwhelmed. The immune system is forced to behave in a weird way because it can't communication properly with the cells it is fighting to protect, due to VP24 is still sitting in STAT1's seat.

"Interferon is critical to our ability to defend ourselves against viruses," said co-author Christopher Basler, a professor of microbiology at Mount Sinai Hospital, in the WU release. "It makes a variety of responses to viral infection possible, including the self-destruction of infected cells and the blockage of supplies necessary for viral reproduction."

Ebola loves not having to deal with the fully functional immune system, because now it can replicate and wreak havoc without interference. This suppression of the innate antiviral immune system (read: interferons) then facilitates a cytokine storm, the paper explains. A cytokine storm is basically too many cytokines (a class which interferons belong to), the result of which is a rapid and potentially deadly immune over-response.

The production of cytokines is a normal response when the immune system encounters an ordinary invader, and their role is to tell your immune cells to go to some location and do their respective immune cell jobs, and also to produce more cytokines. A healthy or at least in-balance body regulates how many cytokines the immune cells create, so they're kept in check. And keeping cytokines in check means keeping the body's immune responses in check.

In a cytokine storm, however, the body never gets the message to stop making cytokines. This results in a positive feedback loop in which the body is telling itself to make more and more cytokines without anything ever telling them to stop. The body's inflammatory immune responses go into hyperdrive, with the results including a skyrocketing fever (potentially deadly in itself) and the rapid build-up of fluids and dead immune cells (pus). Take the shedding of this fluid coupled with a catastrophic decline in the body's blood clotting ability and the result is Ebola's infamous blood spewing from orifices, which, in fairness, is really more of an oozing if it occurs at all.

With these two protein interactions fully described, the task becomes figuring out how to protect the cellular messenger KPNA5's ability to signal and, thus, initiate a normal, controlled immune response. With that response in place, it's possible to imagine Ebola as merely a gnarly but generally survivable viral infection, like a common flu.