Stephen Calderwood Discusses the Infectious Mechanisms of Cholera
Special Topic of Cholera Interview, July 2011
Is the organism trading off long-term survival for short-term infectivity?
That may be the case. One of the interesting things in cholera epidemiology is that we know that cholera was in existence in the Ganges River delta in South Asia for centuries, but wasn't seen in the rest of the world, at least by historical reports, until the 1800s. Then a series of pandemics occurred where cholera would spread widely across the world, causing large numbers of illnesses and deaths. Each of those pandemics from the early 1800s through the early 1900s lasted several years to at most a decade. Then they would go away.
In 1961, a new form of cholera, a new biotype called the El Tor biotype, first emerged as a pandemic strain, and that pandemic has now been going on since 1961. So unlike the previous ones, this pandemic has been going on for over 50 years. That suggests that this new biotype probably has some environmental survival advantages and the disease it causes in humans is a little less severe.
It may be that this new strain of cholera is able to transiently cause an infection, have this hyperinfective state for an intermediate period of time, but then readapt for environmental survival and exist longer in the environment. The El Tor biotype has displaced the earlier classical strain entirely—we don't see that earlier strain in clinical illness anymore.
Is it the first suggestion of hyperactivity that made the 2002 Nature article so highly cited?
I think it was the idea of being able to directly look at what happens to an organism during human infection. Cholera is a particularly good model for studying events directly in humans. When people pass large amounts of watery stool, that stool is comprised almost exclusively of the cholera organisms, and so it's rather easy to take the organism in the actual infectious state without having to culture or modify it in any way and look at how genes are expressed.
This paper was one of the earlier attempts to look at gene expression during infection without introducing any manipulation. I think it was from that, once we realized what kind of genes were being turned on, and that those genes might relate to transmission, that the hyperinfectivity followed. That was only a smaller subsection of that paper. But I think it's the piece that has been more resonant in terms of issues that relate to transmission. It gives an actual model of how transmission might work in the real world.
What are the two or three most exciting or interesting things you've learned about cholera in the nearly a decade since that paper came out?
I'd focus on a couple of things. When you look at people who get cholera, one of the things that's been interesting is that natural infection by the organism protects from symptomatic re-infection for as long as six to eight years. That's quite good protection. So it suggests a vaccination strategy should be effective.
Unfortunately, the killed vaccines that are currently in use, while they do produce protection of perhaps 80 or 85%, the duration of the protection they produce is only in the range of two to three years. That may not be all that helpful as a vaccination strategy in areas that are quite poor. What we've been trying to do is follow very carefully the events that follow natural cholera and try to figure out from them what the actual sequence of immunologic events are that cause this long-term protection with natural infections.
I think we have a reasonable hypothesis, that it's the generation of memory B-cells, either in the circulation or the gut, that are probably responsible for the protection. Generation of an effective memory B-cell response may depend on what happens in the first week or so after infection: first the innate immune response, which then couples to the other arm of the immune response, the T-cell response. These seem to be necessary to trigger the long-term B-cell response that's protective. And when we look at the current killed vaccines, those early events are quite different.
What we'd like to do now is understand those early events in enough detail following natural cholera so that we could figure out a way to restore them or mimic then when you give a vaccine in a way to make protection from the vaccine last longer.
"Cholera is a particularly good model for studying events directly in humans."
That's the first interesting thing that we're now pursuing. The second is an experiment of nature. When you're studying cholera in humans, since you can't experimentally manipulate the variables as you can in the laboratory, you have to look at what possibilities are presented by nature and then design a way to ask a question that might be valuable. One aspect of our studies in Bangladesh is that when we enroll patients with cholera in our longitudinal studies, we also go to their household and enroll the whole household, or at least those who are able and consent.
A few things have come out of those studies. First is that there is an extraordinarily high rate of transmission in the household when an index case is infected—in the range of 30%. That's a very high risk of other people getting ill, much higher than many other infectious diseases.
The second is that because you then have two groups in these households, one that does get subsequent symptomatic infection and the other that doesn't, you can ask whether there are any baseline characteristics that can predict which route they're going to go down. From that, we've been able to figure out the first polymorphism in a human gene that puts people at risk for cholera. We were also able to describe the immunologic markers present in contacts that are associated with protection that came out in some of the work I mentioned earlier. We were also able to measure the effects of vitamin A, for example, or of parasitic infection that might be present, or a variety of other host factors relevant to transmission in this setting.
How much of the variation in transmission can be explained by the polymorphism in that one human gene and perhaps differences in hyperinfectivity individual to individual?
We don’t have the data to answer that. We haven't looked at differences in the excretion of hyperinfective organisms from one individual to another. That's a very interesting question because I assume there probably is variation from person to person. And some people may in fact transmit in the household more frequently than others. But we haven't looked at that at all. We haven't connected hyperinfectivity as a population phenotype to individual transmission risk, or to the polymorphism in the human gene that puts people at higher risk of getting cholera.
What do you consider the major challenges to doing cholera research looking forward to the next decade?
I think the first challenge, of course, is to continue to learn ways to study the disease directly in humans. That does limit the way you can design an experiment. And so we have to be observers of what occurs naturally, rather than being able to manipulate all the variables as we're able to do in animal models and in vitro. Cholera, of course, is a disease that occurs in particular places around the world, so that is where these studies need to be done.