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Paul Ewald: Infectious Disease and the Evolution of Virulence


Q: How does understanding the evolution of virulence help us to manage infectious disease?

A: For most of the last two centuries people have been using interventions to knock down infectious diseases as much as possible. The idea is that we're going to use weapons like vaccines and antibiotics or hygienic interventions to reduce the frequency of infection as much as possible.

My point is that there's another way of controlling these disease organisms. Instead of using these weapons -- antibiotics and vaccines and hygiene improvements -- as a way of knocking down the organism, we can use those interventions to control the evolution of the organisms instead of getting the organisms evolving around our interventions. We can get the organisms to evolve to be less harmful than they have been in the past. Essentially, what I'm saying is we can use interventions like vaccines or like hygienic improvements to domesticate these organisms.

That argument may seem a little bit surprising, but we've already domesticated organisms in many ways. One of the most obvious ways is when we make live vaccines in the laboratory. We're actually taking harmful organisms [and] changing the course of their evolution, making them evolve to be mild enough that we can then introduce them into people as a vaccine.

Q: Give us a new way to look at disease organisms.

A: Some people think that disease organisms are out to get us -- any false move and we'll be damaged or even killed by them. Other people think that disease organisms really, in the best of all worlds, would be so mild that we wouldn't even know that they're there. And the truth is that both of those explanations are right, and disease organisms can be anywhere in between.

I think the right way to look at them is that we're the environment for them and, in some cases, our health is important for their well-being, particularly if their transmission depends on our being healthy. You've got a lot of organisms that are living in and on us that cause us no detectable harm whatsoever.

In fact, we wouldn't want to be getting rid of all of the organisms that live in and on us because many of them are protecting us against other organisms. If we can favor those mild organisms, then they can protect us against the harmful organisms. I think that will be one of the goals of medical work in the next century, especially for those disease organisms that seem to be totally unresponsive to the attacks that we impose on them from antibiotics or vaccines.

Q: Tell us about that transmission strategy -- how a disease organism tries to reproduce, how it tries to get to the next host -- and then tell us how that relates to its virulence.

A: I would say that disease organisms are selected to compete with other disease organisms, that's the bottom line. So if a disease organism is transmitted in a way that requires a healthy host, the best competitors will be those disease organisms that are mild enough to keep their host healthy to allow themselves to be transmitted.

By focusing on the mode of transmission for disease organisms we can gain a lot of insight into why some disease organisms are harmful and other disease organisms are mild. For example, a disease organism like the rhino virus that causes a common cold really does depend on fairly healthy people to be transmitted. So, not surprisingly, the rhino virus is one of the mildest viruses that we know about. In fact, nobody has ever been known to die from a rhino virus, and that's not true for almost any other disease organism of humans for which we have ample information. Almost all the other disease organisms will cause enough damage so that some people might die, if they're particularly vulnerable.

So, in the case of these mild organisms like the rhino virus, if a person happened to be housing a virulent mutant -- these mutants are happening all the time, even in the mild organisms, mutations that might make it a little more harmful or a little less harmful -- then you can ask the question, "Will that organism spread?"

The rhino virus is transmitted when people sneeze on other people, or maybe people sneeze in their hands and then they shake hands with other people, and those people then may touch their nose with those contaminated hands. Given that those are the main routes of transmission, it's clear that if we had somebody who is infected with a particularly harmful variant of the rhino virus, a variant that was so harmful that the person would have to stay in bed, that even though that virus might be reproducing a lot more in the short run, in the long run that organism would lose out in competition. A person who is stuck at home in bed is not going around sneezing on their friends. An immobilized person is not going to be a major source of transmission for something like the rhino virus. That explains why the rhino virus has evolved to be fairly mild.

At the other extreme we've got disease organisms like the protozoan that causes malaria, which can be very harmful. What's especially important in this context is that if the organism is harmful, so harmful that the person can't move from bed, the organism, at least in many parts of the world, can [still] be readily transmitted to other people because a person who's sick, maybe delirious in bed, is a sitting duck for mosquitoes.

Mosquitoes can bite that person more effectively than a person who's feeling very healthy. So in this case we expect that natural selection would actually favor those variants of the malaria organism that exploit the host fairly ruthlessly. A sick person's less likely to swat a mosquito. So, in that case we expect that these disease organisms that are transmitted by vectors, things like mosquitoes, should evolve to be among the most nasty of human pathogens and that's, in fact, what we find.

We find that the vector-borne disease organisms, disease organisms transmitted by things like mosquitoes or sand flies, tend to be much more damaging than the disease organisms that are transmitted by people walking around sneezing or coughing on other people.

Q: Let's talk about waterborne diseases.

A: Diarrheal disease organisms can be transmitted in several different ways, and at least one of those ways also allows the organism to be transmitted from very sick people -- that way is waterborne transmission. If a diarrheal organism is transmitted by water, then even a very sick person can serve as a source of infection for hundreds or even thousands of other people.

How does that work? If you were living in a place like Bangladesh or Ecuador, a place in which water supplies are not well protected, and you imagine somebody who is infected with a particularly ruthless strain of a diarrheal bacterium, that bacterium may be reproducing to a very high level and thereby causing the negative effects that we see in the sick person. In the process of reproducing, it's gaining competitive advantages against other organisms by shedding tremendous numbers, maybe as many as a billion organisms from a single infected individual. And because that person's not moving, those organisms are released into clothing or bed sheets, and they don't stay there -- somebody else will come along, take that contaminated material, maybe wash it in a canal. The canal water may drain into drinking water, or people may come to the contaminated water and gather that water and bring it back in the house. Maybe some system for distributing water will go to a contaminated source and distribute it to large numbers of people. That whole process is analogous to a swarm of mosquitoes moving from one infected individual to large numbers of susceptible individuals.

[We] refer to those cultural analogs of vectors like mosquitoes as "cultural vectors." Waterborne transmission is part of a cultural vector that allows transmission to occur from very sick people, and, in so doing, would tip the competitive balance in favor of the more nasty exploitative variance in the disease organism population. As a consequence, if you have contaminated water allowing transmission of disease organisms, we expect those disease organisms to evolve to a particularly high level of harmfulness, and that's exactly what we see.

If we look at the bacteria that cause diarrhea and we quantify how dependent they are on water as a mode of transmission, we find that the more waterborne bacteria are much more harmful. The worst of all of the diarrheal bacteria that we know of have been waterborne bacteria. [For] example, the bacteria that cause cholera are often waterborne. Bacteria that cause typhoid fever are often waterborne. Bacteria that cause the worst of the bloody diarrheas that we call dysentery are waterborne.

As a consequence, if waterborne transmission [is] very prevalent in an area, then we expect that the diarrheal disease organism should evolve to become more exploitative, using us more extensively as their food sources, and thereby become more harmful to us. If, instead, we clean up the water supplies, then we force the disease organisms to be transmitted only by routes that require healthy people. So what we should be finding if we clean up water supplies is that we drive the organisms to evolve toward mildness.

And that's a very powerful idea, because when you clean up the water supply, the only routes that are left for transmission are routes that require people to be fairly healthy. So the new view would say if you clean up the water supply, we'll get far more benefit than we'd expect, because in addition to reducing the frequency of infection, we'll also mold the organisms -- evolutionarily, we'll force them to evolve to mildness.

The evidence from the literature indicates that, in many cases, we could have forced them to evolve to be so mild that almost nobody would be killed. In fact, most people wouldn't even know they're infected. They would have infections that are asymptomatic; that is, people are carrying around the organism and the organism's generating some immunity in them and so it's providing some protection against the other organisms, but the person who's carrying the organism around doesn't even know that he or she's infected.

Q: Let's talk about disease organisms that can survive outside the host in various conditions.

A: As we look at respira-tract pathogens, we still see a lot of variation in harmfulness of disease organisms. At one extreme we have very deadly organisms like the smallpox virus, or the bacterium that causes tuberculosis. At the other extreme we have the very mild disease organisms like the rhino virus that causes the common cold. So that raises the question: Why do we have this variability? Well, evolutionary theory provides us with an answer. In particular, evolutionary theory focuses on whether a disease organism can be transmitted from somebody who is very ill with an infection.

One of the ways in which disease organisms can be transmitted is by being durable in the external environment. If we imagine a disease organism that could last for 10 years in the external environment, even if a person who's infected is immobilized, coughing or sneezing or shedding one way or another, many people may come to that spot in the next 10 years, so that immobilized person could still serve as a source of infection for many susceptible individuals.

What we expect, if that argument's right, is to see an association between how durable the disease organisms are in the external environment and how harmful they are. And that's exactly what we see. At the top of the list is the smallpox virus, which can last, in some cases, for more than 10 years in the external environment, and it's the most damaging of all the respiratory tract infectious agents of humans. Next on the list would be the tuberculosis bacterium, which is also quite durable in the external environment. It's also a very damaging pathogen.

If we look at disease organisms like the rhino virus that causes the common cold, we find that it loses its viability within a few hours after being sneezed out. So it's not too surprising that it's very mild. It really does depend on people coming in close contact with other people, getting out and moving around in the environment, whereas the virus that causes smallpox doesn't depend on that mobility nearly so much.

Q: Summarize your theory and your ideas natural selection and transmission of disease organisms.

A: We can summarize this information in a nutshell by focusing on how dependent disease organisms are on the mobility of the host for transmission. If a disease organism is very dependent on healthy hosts moving around [and] contacting susceptible hosts, then we expect natural selection to favor extreme mildness in those disease organisms. If, however, the disease organism is not dependent on host mobility -- for example, if the disease organism's transmitted by mosquito, or contaminated water, or because it's durable in the external environment -- then we expect that natural selection will favor high levels of harmfulness in those disease organisms.

Q: Given that we have this information, how do we apply it?

A: Once we understand the factors that favor increased harmfulness and decreased harmfulness, then we can ask the question, "Can we do certain things that would favor organisms evolving toward mildness?"

In some cases we might want to have a harmful organism -- for example, if we were generating an organism to control an agricultural pest. But in terms of human diseases, generally it's in our interest to have the disease organisms be as mild as possible.

What we can do depends on the particular category of disease organism we're looking at. For example, for diarrheal disease organisms, we know that waterborne transmission should favor the harmful competitors among those disease organisms. If we clean up the water supplies, we should be favoring the milder competitors. When we look at the population of disease organisms in any given area, we see both mild and harmful strains. The mild strains are there, sort of hanging on; all we need to do is tip the competitive balance in favor of those mild strains.

One way we can do that is by investing in clean-up of water supplies and also investing in adequate sewage disposal. If we do that, then we should get not only the benefit that most people would recognize -- reduced frequency of infection in the population -- but also we should be molding those disease organisms toward mildness. We should be taking control of the evolution of those disease organisms, favoring those mild strains and thereby essentially domesticating those disease organisms, making them into mild versions of what was there before. With a mild version, most people won't even know they're infected. It'll be almost like those people having a free, live vaccine, and, like a vaccine, those mild organisms can generate immunity that will protect against harmful organisms that might arise through mutation or might come into the area as a result of infiltration from other countries which hadn't cleaned up their water supplies.

We can look at the experience in South America and Central America as a kind of a natural experiment that allows us to evaluate these ideas. In 1991, cholera came into Peru and then quickly, within a couple of years, spread all throughout South and Central America. Some countries had clean water supplies, and other countries had contaminated water supplies. What we find is that when the organism invaded countries with clean water supplies, the organism dropped in its harmfulness.

In contrast, the organisms that invaded countries with poor water supplies, countries like Ecuador, evolved increased harmfulness over time. They've actually become more toxigenic -- they produce more toxin than they did at the outset. So that's very worrisome for those countries with poor water supplies. It means that the next time conditions are ripe for a cholera epidemic, they may have a worse problem than they've had in the past.

Q: Most people don't think that we actually are affecting evolution in any way.

A: Many people think of evolution as something that takes a long period of time, something that might require millions of years. But the truth is that evolution can occur very quickly -- and especially from microbes, it can occur very quickly. One can get evolutionary changes in antibiotic resistance over a period of just a few weeks, if the use of the antibiotic is extensive enough. And so with disease organisms -- because they're dividing so quickly, because they can generate mutations at a rapid rate, because they can share their genetic information among the different members in that population -- evolution can occur very quickly.

We need to think about evolution on a time scale of months to years in terms of our intervention strategies and, unfortunately, people just haven't been thinking about it in that way. Mainly, people have been thinking about evolution as a source of problems rather than a source of solutions. For example, when people are looking at the antibiotic resistance problem, they see evolution as sort of the bad guy -- it's the evolutionary process that's led to antibiotic resistance. That's true, but just as easily we can have evolution being the solution.

In other words, we can have evolutionary processes leading to organisms becoming more mild over time, and if organisms become more mild, then we've solved the problem. Not by getting involved in some kind of arms race in which we're using one antibiotic weapon against the organism, and [the organism] evolving a defensive weapon against that antibiotic, and then we have to shift to another, and so on, indefinitely. Instead, we have a sense of where we want evolution to end, and we adjust the environment so that the organism freely evolves to that endpoint, which is in its interest and also in our interest.

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