Harris, Jason B.

LaRocque, Regina C.

American Journal of Tropical Medicine and Hygiene

Harvard University - DASH 

Cholera and ABO Blood Group:Understanding an Ancient AssociationThe Harvard community has made thisarticle openly available.  Please share  howthis access benefits you. Your story mattersCitation Harris, Jason B., and Regina C. LaRocque. 2016. “Cholera andABO Blood Group: Understanding an Ancient Association.” TheAmerican Journal of Tropical Medicine and Hygiene 95 (2): 263-264.doi:10.4269/ajtmh.16-0440. http://dx.doi.org/10.4269/ajtmh.16-0440.Published Version doi:10.4269/ajtmh.16-0440Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002514Terms of Use This article was downloaded from Harvard University’s DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAAm. J. Trop. Med. Hyg., 95(2), 2016, pp. 263–264doi:10.4269/ajtmh.16-0440Copyright © 2016 by The American Society of Tropical Medicine and HygieneEditorialCholera and ABO Blood Group: Understanding an Ancient AssociationJason B. Harris1,2* and Regina C. LaRocque1,31Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts; 2Department of Pediatrics, Harvard Medical School,Boston, Massachusetts; 3Department of Medicine, Harvard Medical School, Boston, MassachusettsSince the association was first recognized by Barua andPaguio in 1977,1 many investigators have confirmed a stronglink between cholera and the human blood group O pheno-type. Although the blood type O does not affect the riskof being infected with Vibrio cholerae, it has a tremendousimpact on disease severity.2 For example, when cholera wasintroduced into Peru in 1991, individuals with blood type Owere eight times more likely to be hospitalized with severecholera.3 Thus, for individuals infected with V. cholerae,blood type can be a life or death matter.It is also very likely that the association between severecholera and blood type O has impacted our evolutionary his-tory. The lowest prevalence of the O blood group phenotypein the world is in the Ganges delta, where cholera has likelybeen endemic for centuries.4 This suggests that cholera hasleft a genetic imprint in historically endemic areas, andmeans that as cholera spreads to areas with a higher preva-lence of the blood type O, the proportion of individuals withsevere forms of cholera will be higher.In this issue of the American Journal of Tropical Medicineand Hygiene, F. Matthew Kuhlmann and others at WashingtonUniversity take a step forward toward understanding themechanism of the association between blood group and chol-era severity.5 The authors studied the effect of cholera toxinon enteroids—a cell culture model derived from ileal andcolonic stem cells that differentiate in vitro into tissue thatmimics many features of the intestinal surface. Using thisapproach, the team compared the responses of choleratoxin-stimulated enteroids derived from blood type O donorsto responses of identically stimulated enteroids from bloodgroup A donors. The investigators demonstrated a signifi-cantly greater cyclic adenosine monophosphate response tocholera toxin in enteroids derived from blood type O stemcells. The team then demonstrated a similar effect afterconverting a blood type A-derived cell line to a blood typeO phenotypic cell, using clustered regularly interspaced shortpalindromic repeats technology to alter the gene that con-trols glycosylation of the ABO blood group glycans.Taken together, these results provide very convincing evi-dence that cholera toxin exerts a more potent effect on cellsexpressing the blood type O-associated glycan. This fits withthe epidemiologic observation that blood type O only impactsdisease severity, but not the risk of infection. However, thiswork still does not identify the precise mechanism by whichcholera toxin induces a stronger response in the type O cells.In fact, a surprising finding in this study was that the greatereffect of cholera toxin in blood group O-derived cells didnot appear to be linked to the amount of toxin binding tocells, which was similar in both the type A- and type O-derived cells.The Kuhlmann study coincides with interesting workrecently published by Heggelund and others, who reportedthe first high-resolution crystal structure of cholera toxin boundto the A and O blood group glycans.6 Although Heggelund andothers did not evaluate the cellular response to cholera toxin,the authors demonstrated that the toxin binds to the bloodgroup O determinant in multiple orientations and with greateraffinity than it binds to the blood group A determinants.What makes this story even more intriguing is that theABO blood group determinant is not the primary receptorfor cholera toxin. Instead, the cellular response to choleratoxin is derived from the high-affinity binding of the toxin tothe cognate GM1 ganglioside receptor. Thus, it is not clearhow the affinity and orientation of binding to the ABO-related blood antigens impacts the cellular response to chol-era toxin. Perhaps a final step in tying this together at amechanistic level will be understanding how variations in theABO blood group glycans impact the interaction betweencholera toxin and the GM1 ganglioside. For example, thiscould be dependent on toxin binding, but could also bedependent on specific cell surface interactions betweenGM1 ganglioside and the ABO blood group glycans. Thus,it seems likely that there is still more to learn. Hopefully, animproved understanding of the molecular mechanisms ofthis long-observed genetic predisposition to this ancient dis-ease will lead to new approaches for combating this globallyimportant pathogen.Received June 2, 2016. Accepted for publication June 14, 2016.Published online July 11, 2016.Financial support: This research was supported through programsfunded by the National Institute of Allergy and Infectious Diseases(R01AI09924, R01AI103055).Authors’ addresses: Jason B. Harris, Division of Infectious Diseases,Massachusetts General Hospital, Boston, MA, and Departmentof Pediatrics, Harvard Medical School, Boston, MA, E-mail:jbharris@partners.org. Regina C. LaRocque, Division of InfectiousDiseases, Massachusetts General Hospital, Boston, MA, and Depart-ment of Medicine, Harvard Medical School, Boston, MA, E-mail:rclarocque@mgh.harvard.edu.This is an open-access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricteduse, distribution, and reproduction in any medium, provided theoriginal author and source are credited.REFERENCES1. Barua D, Paguio AS, 1977. ABO blood groups and cholera. AnnHum Biol 4: 489–492.2. Harris JB, Khan AI, LaRocque RC, Dorer DJ, Chowdhury F,Faruque AS, Sack DA, Ryan ET, Qadri F, Calderwood SB,2005. Blood group, immunity, and risk of infection with*Address correspondence to Jason B. Harris, Division of InfectiousDiseases, Massachusetts General Hospital, 55 Fruit Street, Boston,MA 02114. E-mail: jbharris@mgh.harvard.edu263vibrio cholerae in an area of endemicity. Infect Immun 73:7422–7427.3. Swerdlow DL, Mintz ED, Rodriguez M, Tejada E, Ocampo C,Espejo L, Barrett TJ, Petzelt J, Bean NH, Seminario L, 1994.Severe life-threatening cholera associated with blood group Oin Peru: implications for the Latin American epidemic.J Infect Dis 170: 468–472.4. Glass RI, Holmgren J, Haley CE, Khan MR, Svennerholm AM,Stoll BJ, Belayet Hossain KM, Black RE, Yunus M, Barua D,1985. Predisposition for cholera of individuals with O bloodgroup. Possible evolutionary significance. Am J Epidemiol121: 791–796.5. Kuhlmann FM, Santhanam S, Kumar P, Luo O, Ciorba MA,Fleckenstein JM, 2016. Blood group O–dependent cellularresponses to cholera toxin: parallel clinical and epidemiologi-cal links to severe cholera. Am J Trop Med Hyg 95: 440–443.6. Heggelund JE, Burschowsky D, Bjørnestad VA, Hodnik V,Anderluh G, Krengel U, 2016. High-resolution crystal struc-tures elucidate the molecular basis of cholera blood groupdependence. PLoS Pathog 12: e1005567.264 HARRIS AND LAROCQUE

Cholera and ABO Blood Group: Understanding an Ancient Association

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