Scientists have found that cholera toxin hyperactivates a key molecule in people with blood type O, causing them to get more severely ill from the deadly disease than people of other blood types.
High levels of that signalling molecule in intestinal cells lead to excretion of electrolytes and water - in other words, diarrhoea, researchers said. Cholera is marked by severe diarrhoea that can lead to dehydration, shock and even death.
"We have shown that blood type influences how strongly cholera toxin activates intestinal cells, leading to diarrhoea," said James Fleckenstein, associate professor at Washington University School of Medicine in the US.
Cholera sickens three to five million people around the world every year, leading to 100,000 to 120,000 deaths, many of them in the Indian subcontinent, where cholera has been endemic for centuries, researchers said.
The disease is caused by Vibrio cholerae, a bacterium that infects cells of the small intestine.
Epidemiologists first noticed four decades ago that people with blood type O were more likely to be hospitalised for cholera than people of other blood types, but the reasons for the difference had never been determined.
Although the blood group antigens - A, B, AB and O - are best known for their presence on red blood cells, they also are found on the surface of many other cell types, including the cells that line the intestine.
To find out what effect cholera toxin had on intestinal cells carrying different blood group antigens, researchers used clusters of intestinal epithelial stem cells, called enteroids, that can be grown in the lab and differentiated into mature intestinal cells.
They treated four groups of enteroids with cholera toxin - two derived from people with blood type A and two from people with blood type O - and measured the amount of a key signalling molecule inside the cells.
The researchers found that levels of the signalling molecule were roughly twice as high in the cells with the type O antigen than in the cells with type A antigen, suggesting that people with type O antigen who were exposed to cholera toxin would suffer more severe diarrhoea.
"It is well-established that high levels of this molecule lead to diarrhoea, so we're making the assumption that higher levels lead to even more diarrhoea," said F Matthew Kuhlmann, from Washington University.
"We have no way directly to link the responses to the volume of diarrhoea and, therefore, the severity of disease," Kuhlmann said.
The researchers confirmed their results in an intestinal cell line originally derived from a person with blood type A, which was modified to produce the type O antigen instead.
They found that cholera toxin induced roughly double the amount of the key signalling molecule in cells with type O antigen than in those with type A.
The findings appear in The American Journal of Tropical Medicine and Hygiene.
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