Nov 11 2010
f you had to make a wild guess about the target of a certain drug, your best odds are with the G-protein coupled receptor (GPCR). Drugs targeting members of this integral membrane protein superfamily, which transmit chemical signals into a wide array of different cell types, represent the core of modern medicine. They account for the majority of best-selling drugs and about 40% of all prescription pharmaceuticals on the market . (1)
It is an interesting fact that far the most prevalent disease associated with alteration in G-protein activity and amount is cholera, a disease that is assuming serious proportions in hurricane-ravaged Haiti. Cholera strikes so fast it is sometimes called the lightening disease. Without rehydration therapy, or antibiotics for severe cases, cholera can kill in a matter of hours. The disease causes acute diarrhea that can lead to severe dehydration. Haiti’s minister of health is calling the epidemic a national emergency. Nearly 10,000 people have been hospitalized since the outbreak began late last month.
G-protein is activated by the exotoxin of Vibrio cholerae, which is ingested via contaminated water, and results in the persistent stimulation of cellular activity. This produces extrusion of water from cells of the intestinal epithelium and the watery diarrhea and dehydration associated with the condition. A number of other bacterial exotoxins can produce similar effects via the same mechanism. (2)
The carbohydrate surface of the intestinal epithelial cells is the site of attachment of cholera toxin, the protein secreted by V. cholerae. Cholera toxin belongs to a distinct group of naturally occurring sialic-acid-binding lectins that includes Sambucus (elderberry) lectin, wheat germ agglutinin, the selectins, most arthropod lectins, tetanus toxin (Clostridium tetani), botulinum toxin (Clostridium botulinum), pertussis toxin (Bordetella pertussis) Influenza A and B viruses hemagglutinins, polyomaviruses, rotaviruses and hemagglutinin neuraminidases and the siglecs (sialic acid–binding, immunoglobulin-like lectins).
Cholera toxin remains a significant cause of gastrointestinal disease globally, particularly in developing countries where access to clean drinking water is at a premium. Vaccines are prohibitively expensive and have shown only short-term protection. Climate change has the potential to increase the threat of water-borne diseases, through rises in temperature and sea-level, and precipitation variability.
Cholera and ABO Blood Group
If you are blood type O, you may want to postpone that trip to Haiti.
Blood group O individuals have a greater risk of infection with cholera and develop the most severe and life threatening forms of this illness. Type O had more diarrhea-like stools per day than persons of other blood groups, and were more likely to report vomiting and muscle cramps.
At the Matlab Hospital of the International Centre for Diarrhea Disease Research, Bangladesh, the blood groups of patients hospitalized between January and September 1979 for diarrheal disease due cholera was examined. A significant association was identified only for cholera, in which cholera patients were twice as likely to have blood group O and one-ninth as likely to have blood group AB as community controls. (3) Cholera infections are particularly severe for blood group O individuals, who are less protected by the current vaccines. (4)
A follow-up study of family contacts of cholera patients, carried out between September 1980 and July 1982, indicated that blood group did not affect an individual’s risk of having a culture-proven infection with V. cholerae but was directly related to the severity of disease. Individuals with the most severe diarrhea compared with those with asymptomatic infection were more often of blood group O (68% versus 36%, p less than 0.01) and less often of AB (0% versus 7%, p less than 0.01). The constant selective pressure of cholera against people of O blood group may account in part for the extremely low prevalence of O group genes and the high prevalence of B group genes found among the people living in the Gangetic Delta.
A household survey at the onset of the 1991 Latin American cholera epidemic, investigated the surprisingly high attack rates in Trujillo, Peru. It showed an association between blood group O and severe cholera. Of 463 persons in 69 households, 173 (37%) reported diarrhea, 21% required rehydration therapy, and 4% were hospitalized; these treatment requirements greatly exceeded estimates based on other populations. Elevated anti-cholera antibody titers were present in 52% of 321 from whom serum was obtained; 73% were blood group O. Blood group O was strongly associated with severe cholera: Infected persons had more diarrheal stools per day than persons of other blood groups, were more likely to report vomiting and muscle cramps, and were almost eight times more likely to require hospital treatment. Group AB seemed to have the least problematic symptoms.(5)
Since prevalence of blood group O in Latin America may be the world’s highest, it is thought that this explained the higher mortality observed in the Peruvian outbreak.
- Milligan G, Kostenis E. Heterotrimeric G-proteins: a short history. Br J Pharmacol. 2006 Jan;147 Suppl 1:S46-55.
- Sinclair HR, de Slegte J, Gibson GR, Rastall RA. Galactooligosaccharides (GOS) inhibit Vibrio cholerae toxin binding to its GM1 receptor. J Agric Food Chem. 2009 Apr 22;57(8):3113-9.
- Glass RI, Holmgren J, Haley CE, Khan MR, Svennerholm AM, Stoll BJ, Belayet Hossain KM, Black RE, Yunus M, Barua D. Predisposition for cholera of individuals with O blood group. Possible evolutionary significance.Am J Epidemiol. 1985 Jun;121(6):791-6.
- Holmner A, Mackenzie A, Krengel U.Molecular basis of cholera blood-group dependence and implications for a world characterized by climate change. FEBS Lett. 2010 Jun 18;584(12):2548-55.
- Swerdlow DL, Mintz ED, Rodriguez M, Tejada E, Ocampo C, Espejo L, Barrett TJ, Petzelt J, Bean NH, Seminario L, et al.Severe life-threatening cholera associated with blood group O in Peru: implications for the Latin American epidemic.J Infect Dis. 1994 Aug;170(2):468-72.