Researchers Narrow in on Genetic Key to Cholera Immunity

Cholera may be prevented by a series of genetic changes, researchers have found -- a discovery that could aid scientists in the quest for the holy grail in warding off the deadly disease.

The team of scientists leading the study gathered genetic data from hundreds of people in Bangladesh and, in doing so, was able to identify a number of areas in the genome -- some responsible for certain immune system functions and others related to fluid loss -- that appear to be related to cholera resistance.

Sure enough, later testing revealed genetic differences between people who had contracted the disease and those who had been exposed but did not become ill.

"This study is exceptionally exciting for us because it shows the power of this approach," said Pardis Sabeti, an associate professor of organismic and evolutionary biology at Harvard University and one of two senior co-authors of the paper. "This is the first time we've taken a genomic-wide approach to understanding cholera resistance."

The hope, Sabeti explained, is that by better understanding some people's apparent immunity, researchers will be further guided in their efforts to develop vaccines and therapies.

"It is a very scary disease," she said. "We now have treatments with oral rehydration therapy, but it is still devastating, and in extreme cases, cholera can kill in hours."

According to Elinor Karlsson, a post-doctoral fellow in organismic and evolutionary biology and the first author of the report, the vaccine currently in use fails to protect against the disease to the same degree as some individuals' immune systems -- a discrepancy scientists would like to see ended.

"The vaccine that's available wears off after a few years, whereas people who are exposed to the disease develop a long-lasting immunity," she said, "and nobody is quite sure why that is. This research is another way of tackling that problem, and it's a way no one has come at it before."

To understand the genetic differences between those with a natural resistance to cholera and those without, researchers first gathered genetic data on 42 family groups -- called "trios" -- that included a mother, father and child.

Using this information, the team of researchers identified more than 300 areas of the genome that appeared to be under pressure due to natural selection, suggesting that genes in those regions might be adapting to deal with the threat of cholera.

And while this is certainly an important discovery, Karlsson admits that "unfortunately, all our tests can tell us is that a region is under selection, it doesn't tell us why."

To find those answers, Karlsson turned to a process called "gene set enrichment" testing to determine whether any particular groups of genes showed up more frequently than its peers.

In doing so, the scientists found two distinct patterns.

"We found a whole set of genes that are related to a gene called IKBKG, which plays a key role in immunity," Karlsson said. "But what we found was not the gene itself, but a whole group of genes that regulate IKBKG."

In addition, the researchers found a whole set of genes for potassium channels, or the channels in the walls of our cells that regulate fluid loss.

"What's interesting is that it shows what a huge pressure cholera has been on this population," she added. "You could be selecting for anything in there -- skin color, hair color or even other diseases -- but because cholera was a big enough force, we could pick it out just by doing this kind of testing."

Armed with that data, researchers then performed a comparative study in which they examined the specific genetic regions in more than 100 patients who were sick with cholera and others who had been exposed to the disease, but had not become sick.

The results, Karlsson said, showed differences between the two groups.

"The region that had the biggest signal that suggested the region was under pressure from natural selection, also had the biggest difference between people who were sick and who were not sick today," she explained.

Going forward, the scientists hope to conduct wider studies on the genetic differences between people who are susceptible and those who appear to be immune to the disease in order to identify exactly which genes are involved, and the pathways involved in resistance.

"We have narrowed it down to a few genes, but the problem is that these are genes that people have not paid a great deal of attention to before," Karlsson said. "There's not a whole lot of description out there about them, so it's hard to know which one might be the best candidate for study."

Ultimately, Sabeit notes, the study is only "a first step, and there is a lot of exploration to go from here. For a disease that's so ancient and widespread there's very little that's known about host immunity."