Immunology

Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)

Please can you give a brief introduction to the Ebola virus?

Ebola virus belongs to a group of viruses that have been known for some time. It was first isolated as a result of an infection in a primate, in a monkey colony, in monkeys that were being used for research in the Philippines.

In that case, although the animals became sick, no humans did. That particular strain of virus does not cause illness in humans, as far as we know.

After that, the first appearance of Ebola virus in humans was in late 1976, where there was an outbreak that led to a significant number of deaths, and that alerted people to the appearance of this new virus and focused a lot more attention on it.

It belongs to a group of viruses that has a very limited number of members that we’ve identified so far.

It’s clear that the virus does not have humans as its natural hostâ€"it has a different host which is its natural hostâ€"and that humans encounter this virus probably because of their incursions into areas where the host animal exists, and so the virus is transferred to humans, or by coming into contact with the host animal directly through hunting or some other activity.

When the virus infects humans it causes a pretty devastating disease called Ebola virus disease. It’s in a group of diseases that we call hemorrhagic fevers because the patient goes through a series of symptoms starting from fairly general symptoms we’d all be familiar with of feeling unwell to becoming seriously unwell.

Then the circulatory systemâ€"the blood system, the blood vessels that contain the blood systemâ€"starts to break down in the latter stages of disease and the patients give the appearance of bleeding from different parts of the body, hence the hemorrhagic disease.

The virus is very efficient at being transmitted by a very limited number of routes. You have to come into contact with contaminated body fluids but that’s an efficient route for them and, in those circumstances, the virus is transmitted pretty well.

Once it infects, in most cases, in the group of individuals it infects, a very high proportion suffer a fatal disease.

Are primates the natural host?

No. Ebola was first isolated in primates that were used for research. In the wild it clearly can infect primates and, in those cases, it kills the primatesâ€"the large monkeys. That’s a serious problem because there have been many incidents of gorillas, wild primates, dying as a result of the disease.

That strongly suggests they are not the natural hosts, because what you see with viruses is that, having been introduced to a host, if they stay within that host they adapt and don’t cause such severe disease.

If you find a virus that causes a very severe disease it usually is an indication that’s not the natural, normal host.

So which animal is thought to be Ebola’s natural host and how was it introduced into human populations?

The answer is yet unknown, but all of the indications point to it being a species of fruit bat that exists in Central Africa in particular.

These fruit bats are somewhat isolated animals. They roost in isolated areas where there’s not much contact, but as humans move into these areas where the bats are found they come in contact with them, and also in some communities bats are eaten as a source of food. They’re quite large; they can have a wing span of two feet across. They’re not like the bats you and I are familiar with.

In some communities and some parts of the world they’re considered a form of food, a basis of food, and that’s certainly true in some parts of West Africa. When we talk about bushmeat most people tend to think of meat coming from four-legged animals, probably with horns, but actually it covers a much broader range of animals. It covers monkeys, of course, but it also covers things like bats.

When was the first outbreak of Ebola in humans and how many individuals have been affected since then?

The first known outbreak, where it was identified, was in the latter months of 1976 and that occurred in the Democratic Republic of Congo.

The first outbreak, that brought everyone’s attention to the virus, was fairly large. Almost 400 people were infected and about 90% of them died.

Of course, at that time, we didn’t know a great deal about the virus; we didn’t really know what it was.

Since then, there have been some two dozen outbreaks varying in size, scale and severity, but to date, including the most recent outbreak, there have been almost 3,000 individuals infected. That's strongly suspected or clearly identified as being Ebola-related infections and, of those, 67% have died.

Please can you outline the range in the scale of outbreaks and the associated mortality?

There has been quite a considerable range. There have been odd, isolated single cases which, depending on the particular strain of virus, either have or have not caused fatality.

The largest outbreak, in terms of cases, was a little over 400 people and that was around the year 2000, about the turn of the century.

In terms of the mortality, if we put aside the occurrences where it’s one or two people because those numbers aren’t really very firmâ€"if one person dies it’s 100% mortality, but it’s not a good statisticâ€"overall, the average mortality has been 67% but, in reality, that ranges from as low as about 25% up to 90%. It’s more commonly at the upper end of that scale than the lower end.

Does the associated mortality depend on the strain of virus?

A little, but only a little. There’s one strain that has only had one or two cases and there have been no fatalities with it.

The other strains always have fatalities associated, but it doesn’t seem to be just strain-dependent; there seem to be other factors which will be many and varied.

It will depend on the precise circumstances: the nature of the community in which the outbreak has occurred, how large that community is, what contact they have, but what their general physical health is as well. That contributes to it.

There are a number of different factors which make it a quite complex interplay determining the outcome.

How has our understanding of the Ebola virus developed?

When it first appeared in humans it was relatively quickly identified as being Ebola, because we knew Ebola existed due to the outbreak in the monkey colony. It wasn’t known at that point that it could affect humans with such devastating consequences.

Since then, we’ve been able to understand a great deal about the molecular detail of the virus: what makes it up, what it looks like, and what components form the virus; a lot of intricate molecular detail that lets us understand how it grows.

We have also learned a fair amount about how the virus causes the disease that we see in patients and it does that by subverting natural systems in the way that many viruses do.

A lot of the aspects of the disease are our own body’s response to the infection. It’s stimulating, in a very abnormal way, natural responses and making them behave aberrantly, and that causes significant damage.

We have a lot of information about that. We've developed very good diagnostic techniques so we can identify the virus as Ebola and, because technology has moved on, we can identify a lot of aspects of the viruses causing each independent outbreak.

We've done a lot as far as that’s concerned, in understanding the virus itself and the disease it causes. What hasn’t kept pace with that is devising preventatives and real treatments that will stop the infection.

How many virus strains have been associated with human infection and how do the distinct strains differ?

There have been five strains identified as being capable of infecting humans, in principle, but only three of them are actually associated with disease.

When we look at these five viruses they are very, very similar to each other and, of course, they can all infect humans.

The question is, why do some cause disease and why do some not? That’s a significant question which is not yet fully understood.

There are lots of factors at play here determining how a virus causes a disease. Some of the factors are determined by the nature of the virus, but also the way in which it interacts with the humans and which elements of the humans can respond to it in the patients that are infected.

It’s a kind of battlefield and with three of the strains all the heavy armaments are in the hands of the virus, and then with the other two strains our armaments are good enough to keep it under control and suppress it so it doesn’t cause these aberrant reactions that lead to the disease. You still get infected, you just don’t get sick.

What are the main hurdles in identifying the Ebola virus strains in isolated rural areas of Africa?

The major problem here is accessibility. They are isolated and rural areas so the infrastructure is limited.

In a lot of these areas there’s no hospital, in the way that we would understand a hospital; they have medical centers but obviously they can’t be fully equipped with the full range of technologies and the technological systems that you get in a major urban center, so the diagnostic capacity in these rural areas is very, very limited and is often nonexistent.

The problem is, when an outbreak occurs, there is a period in the early stages where the patients are presenting with general symptoms which are familiar to us all and reflect lots of different types of infections. You don’t know what’s causing it, so there’s a lag stage where it’s not clear what’s going on.

Then you start to see the signs of severe disease, the numbers begin to increase and then you’ve got a problem: a problem of then getting patients to places where they can be dealt with; where they can be isolated, amongst other things; and where they can be nursed under appropriate controls. These are very sick people, so that’s not easy.

The resources are not there to move these patients, so getting access to material from the patient in the right form, at the right time in the infection, is quite difficult.

Then it has to be transported from there to the central location where the diagnostic procedures are carried out, because these tend to be in focal regions.

It’s a slow process and by the time you get a clear diagnosis the infection is already well established usually. By then there are very strong suspicions as to what it is simply by the clinical presentation, and the diagnosis is a confirmation.

How important is rapid diagnosis early in an outbreak?

It’s extremely important because, at the moment, the best way to stop an outbreak from spreading is to stop the virus from transmitting from one individual to another.

To achieve that you have to have a number of things in place. One, you have to be able to identify the infected individual as early as possible after infection. That may be before they present with the most severe symptoms.

To do that you need good diagnostic techniques and understanding of what’s going on. That allows you, in the case of Ebola, to segregate those infected individuals from the general population and to provide nursing with the appropriate barriersâ€"containmentâ€"to prevent the health care staff, who may themselves be at risk, from becoming infected.

If what you’re trying to do is break the transmission of the infection from one individual to another then the earlier you get the diagnosis, and the more accurate that diagnosis, the more effective the intervention.

How far have treatments advanced?

In all honesty, not very much at all. First of all, there’s no vaccine to prevent the infection and there’s no drug available to treat it afterwards.

Treatment really is supportive and trying to prevent the infection from spreading to someone else.

I’m afraid that’s true for lots of viral infections and I wouldn’t pick out Ebola as being unusual in this regard.

If you look across the planet and ask how many drugs there are to treat viruses, the answer is less than thirty. If you ask how many viruses can be treated by drugs, the answer is considerably less than ten, so Ebola is not unusual in this regard.

Why are viruses so hard to treat?

They’re hard to treat because they’re parasites and they’re true parasites in that, when they infect, they actually go inside our cells and they use the processes that we use naturally. They simply take them over.

If you’re trying to kill a virus by attacking its replication processes, the processes that make it multiply, those are the same processes we use so you may kill the virus very successfully but you could seriously damage, potentially even kill, the host.

They become so intimately involved with the mechanisms of the host that it’s very, very hard to attack them without causing damage to the host and so it’s a very complex process. It makes a fascinating study, of course, but that’s no help to the infected people.

How do drugs for other viral infections work?

The best example, of course, is for HIV. The way that they work is because HIV does become intimately associated with the host but it also makes some proteins called enzymes that it needs in order to grow.

There are a limited number of those proteins that it makes, there are only three or four, but we’ve been very successful, because of the sheer weight of effort into it, in identifying drugs that inactivate those.

The issue with viruses is that they’re very clever, in an evolutionary sense. If you make a drug that attacks a particular enzyme of a virus, what you find is that, very rapidly, that virus evolves resistance.

One drug invariably is not enough. You actually need several if you’re going to be really effective. HIV patients are given three drugs simultaneously. That’s why they work.

Has there been an improvement in the prevention of transmission of the Ebola virus between people?

There has, in as much as we now understand what the source of the virus is when it’s moved from one person to another: it’s body fluids. That’s very well understood now.

For example, in some of the communities that have been hardest hit, they had some religious processes that required them to handle bodies, for burial and so on, in certain ways. Those procedures put them at risk, so understanding what the risk is and informing people can help them with that.

There were also some other ritualistic processes that increased the risk and also blood test contamination and so on.

The other thing that’s become clear over recent years is that the people who survive, this small fortunate number of people who survive, still secrete virus for some weeks after they get better. That’s unusual in these sorts of infections.

This is particularly true in men because the seminal fluid that they produce contains virus for up to six or seven weeks after they’ve recovered, so the virus can be transmitted sexually from males during that period particularly.

There are other routes as well, but this understanding that, even once you’ve recovered, you still pose a risk to the community through certain activitiesâ€"not general activities, but through certain activitiesâ€"has been quite important in trying to inform people where the risks lie and that helps the situation.

You can imagine, without that knowledge, if there was a small outbreak there’d be some survivors and then five weeks later they could reintroduce it into another group of people and then there’d be another flare-up, and then another flare-up, and it never really would die away.

An understanding of how it’s transmitted can really help in bringing an outbreak to an end.

What do you think the future holds for Ebola research?

There’s still the question of where it comes from and what the risks and exposure risks are from that source, so that has to be looked at. Although I think that, by and large, we’re getting there with that.

The real thing is to try and devise some method of treatment for the affected people. The ideal would be a vaccine to prevent it but there are some logistical issues with that, mainly to do with the financial implications.

The scope, I think, is for developing approaches to treatment that could reduce the mortality - I don’t think they’ll eliminate it but they will reduce it - and really reduce the impact of this virus on these communities that are exposed to it.

What’s the likelihood of Ebola being transmitted to another part of the world? For example, what if someone infected with Ebola gets on an airplane?

You can never rule these things out completely, but it is not a virus that’s likely to spread really rapidly and broadly in the wider community.

We can see that, even in the communities which have limited access to health care mechanisms, it’s controlled and contained. In other communities you would expect the same.

Of course, it’s not something we want to test. I think that scenario is unlikely.

Is Ebola likely to become airborne at any point in the future?

Ebola has had millennia to become airborne and it hasn’t; it’s not going to become airborne just because that would be bad for us.

Viruses have evolved to have certain routes of transmission. They do not change those routes readily.

These outbreaks are huge tragedies, there are a large number of people who have suffered terribly as a result, but in the scheme of the life cycle of this virus we’re a sideshow. We’re a side effect; we’re nothing else.

We’re not a major player in the life cycle of this virus. It does not need to infect humans to survive. The evidence of its survival is that it periodically infects us.

Where can readers find more information?

There are two very good sources of information. The first one I would suggest is the World Health Organization. Their website has a really excellent resource of information that gives what you need to know about outbreaks: where they’ve occurred, when they’ve occurred, the severity of them and so on. From there it’s possible to find links to other aspects of the virus.

The other is the United States Centers for Disease Control, which has very similar levels of information. A lot of the studies of the viruses were carried out in CDC in Atlanta. They have a long term interest and when outbreaks occur they often send staff over to share their experience and knowledge, so they’re a great resource of information.

About Professor Easton

I obtained a PhD in virology from the Medical Research Council Institute of Virology in Glasgow. Following that I undertook a period of postdoctoral research, studying interferon genes, in a pharmaceutical company before joining the Virology Research Group at Warwick University as a lecturer in virology in 1983. Since being at Warwick I have primarily on viruses that infect the respiratory tract, primarily influenza virus and respiratory syncytial virus. Both are responsible for serious respiratory disease. More recently I have also begun work on a virus called Chandipura virus that is found predominantly in certain parts of India and has been associated with the neurological disease encephalitis in young people. All of my work has focussed on understanding the molecular mechanisms that viruses use to replicate within the cells of their human hosts.