Connection Between Blood Type O and Cholera Explained in New Study

According to the World Health Organization (WHO), cholera sickens 3 to 5 million individuals every year, and causes 100,000—120,000 deaths worldwide. For those infected who also have blood type O, the disease is likely to be more severe.

Many investigators have confirmed the link between Cholera and individuals with blood type O, since the association was first recognized in 1977. Although people with blood type O are not at greater risk of being infected with Vibrio cholerae, it may have an impact on the severity of the disease.

Researchers from Washington University in St. Louis believe, “It is also very likely that the association between severe cholera and blood type O has impacted our evolutionary history. The lowest prevalence of the O blood group in the world is in the Ganges delta, where cholera has likely been endemic for centuries.”

This suggests that in historically endemic areas, cholera has genetically imprinted itself on those populations. This also means that as cholera spreads to areas where many more people have the blood type O, the severity of cholera will be higher.

James Fleckenstein, MD, senior author and associate professor of medicine and molecular microbiology at Washington University in St. Louis, and colleagues have made strides in understanding the association between blood group and cholera severity. Studying “the effect of cholera toxin on enteroids—a cell culture model derived from ileal and colonic stem cells”—allowed the team to “compare responses of cholera toxin-stimulated enteroids in blood type O donors and responses of identically stimulated enteroids” from donors with blood type A.

The researchers found a “significantly greater cyclic adenosine monophosphate response to cholera toxin in enteroids derived from blood type O stem cells. [They] then demonstrated a similar effect after converting a blood type A-derived cell line to a blood type O phenotypic cell, using clustered regularly interspaced short palindromic repeats technology to alter the gene that controls glycosylation of the ABO blood group glycans.”

According to the researchers, these “results provide convincing evidence that cholera toxin exerts a more potent effect on cells expressing blood type O-associated glycan.” Given the “epidemiologic observation that blood type O” only makes the disease more severe, and does not put a person in the blood group O at higher risk for infection, this fits, however it does not identify a precise mechanism by which cholera toxin induces such a severe response.

This study coincides with recently published work by Heggelund and his team, who reported the first high resolution crystal structure of cholera toxin bound to A and O blood group glycans. Although that research did not evaluate the cellular response to cholera toxin, the authors showed that the toxin binds to the blood group O in multiple orientations and with greater affinity.

Intriguingly, the ABO blood group determinant is not the primary receptor for cholera toxin. Instead, cellular response to cholera toxin is derived from the high-affinity binding to the cognate GM1 ganglioside receptor.

It is still unclear how “affinity and orientation of binding to the ABO-related blood antigens impacts the cellular response to cholera toxin.” However, the authors conclude, “[a]n improved understanding of the molecular mechanisms of this long-observed genetic predisposition to this ancient disease will lead to new approaches for combating this globally important pathogen.”

Editor's note: ContagionLive originally reported that Dr. Fleckenstein was located at Washington State University. That information was incorrect. The article had been updated to reflect his correct institution: Washington University in St. Louis.