U of T researcher: Ebola is a ‘Clever’ Virus

Q&A with Structural Virologist Professor Jeffrey Lee

How does Ebola virus evade the immune system? How can we treat it in the future? Professor Jeffrey Lee, a researcher and Assistant Professor in the Department of Laboratory Medicine and Pathobiology, answers these important questions and takes us on a journey into the molecular world of Ebola virus.

Professor Lee studies how viruses, like Ebola and retroviruses, enter healthy cells and how our immune system reacts. Using a technique called protein X-ray crystallography and other biophysical techniques, he renders every atom of the protein and creates a highly accurate three-dimensional model. This model reveals vulnerabilities of the disease and provides a blueprint for effective drug development.

Ebola virus kills up to 90% of its victims, and as of August 12, 2014, the World Health Organization has confirmed 1,848 cases and 1,013 deaths in the most recent outbreak in West Africa. While two infected American aid workers and one Spanish priest were treated with an experimental antibody therapy, there is no widely-available approved treatment.

What do you find most interesting about Ebola?
It’s cleverness. It only has seven genes—that’s almost nothing compared to us—yet it has so many elegant ways to escape and counteract our immune system.
In order to spread, Ebola virus needs to transmit its genomic material into healthy cells. This is accomplished when a flower-shaped protein on the surface of the virus binds to receptors on healthy cells—it’s like a lock and key.

But Ebola virus is clever because it disguises its surface flower-shaped protein with sugars and this allows it to evade the immune system. If the immune system recognizes these proteins, it will attack and destroy the virus. Essentially, this sugar protein or “glycoprotein” looks like a cotton candy ball and the protein underneath will be protected.

Another strategy to evade the immune system is that the virus can release glycoproteins that are similar to the ones found on its viral surface. These shed glycoproteins can then become decoys by soaking up antibodies. Brilliant. Just a brilliant piece of engineering. If you told me to design a protein that could do this—no way. We have a number of countermeasures for foreign pathogens, but Ebola virus has come up with solutions to most of them.

How can we target this evasive virus?
There is this one little patch at the bottom of the glycoprotein which isn’t disguised by sugars. It’s Ebola virus’s Achilles’ heel. The two patients medically evacuated to Atlanta, who were infected in Africa, were treated with an experimental cocktail of three antibodies (ZMapp)—some of which likely target this site.

What is an antibody treatment?
Antibodies are part of our adaptive immune system and are one of our primary responses to a foreign pathogen. Antibodies are able to seek out the virus and bind tightly to the viral glycoprotein to then target the virus for destruction. The ZMapp antibody cocktail is very specific to Ebola virus and there are likely few side-effects. 

Why aren’t we currently using this treatment for all infected patients?
Currently, the treatments are experimental. While it’s a highly effective treatment in non-human primates, we don’t know whether this will translate in humans. Antibody treatments in general are very expensive and can run into the tens of thousands of dollars to treat one person. Given that this treatment is still under development, there is also a short supply of the antibody cocktail.

Also, transporting antibodies to small villages in Central and West Africa is a major logistical issue. Antibodies are proteins that need to be refrigerated. Some of these areas might not even have running water let alone refrigeration.

What other treatments would be more practical?
An alternate treatment would be to develop traditional small molecule drugs that could remain stable at room temperature for a long time. Unlike antibodies, these drugs can also penetrate the membrane of the cell and thus exploit other targets inside. But the challenge with this approach is it often takes 15 years of development and clinical testing, plus billions of dollars, to bring this type of drug to market.

Why is Ebola so virulent?
Ebola virus is fairly stable and the virus can survive in various environmental conditions. The Ebola virus glycoprotein itself is extremely stable and resistant to very harsh conditions. It’s not like HIV that can just fall apart in the air.

With Ebola virus, you only need one viral particle to be infected. Another problem is that Ebola virus hits almost all of your cells and it replicates rapidly. There’s also 21 day incubation period. You might not know you’re infected or you may think you just have a cold. If you travel, there is the potential to spread it to other countries.

If we can easily treat Ebola, can we treat other viruses the same way?
Both Ebola and Marburg viruses are viral hemorrhagic fevers that belong to the filovirus family. There have been suggestions that if you develop a drug against the receptor for Ebola virus, it should work against Marburg virus as well because they share a common receptor.

However, it’s unlikely that a treatment used for Ebola virus would work for other viruses. Unlike antibiotics, we don’t have any broad-spectrum anti-virals. Viruses are all very different; they have various entry mechanisms as well as replication strategies. We likely need a different drug for all of them. On top of this, viruses often mutate and a drug that once worked might become ineffective.
Moving forward, how can we prepare for similar outbreaks?

In the meantime, the best practice would be to have good infection control and containment in place. But of course, a priority would be to characterize the ZMapp antibody cocktail and figure out whether it is effective. There’s also likely going to be more money put into this area to develop new countermeasures and to push existing ones into the clinic. Essentially, it’s an arms race and whoever has the bigger gun will win.

Image 1: Figure of the Ebola virus surface glycoprotein (GP) bound to an antibody identified from a human survivor. The sugars that decorate the GP surface are shown as yellow balls.
(Lee et al. 2008 Nature 454. 177-82.)

Image 2: The molecular model of Ebola virus glycoprotein. This is the protein that sits on the surface of the Ebola virus and facilitates its attachment and entry into human cells.
(Lee et al. 2008 Nature 454. 177-82.)