Cholera and genetics

DEFINITION Cholera is an infection of the small intestine caused by the comma-shaped bacterium Vibrio cholerae. Cholera arose centuries ago in India and was disseminated throughout Asia and Europe by trade and pilgrimage. It was devastating, causing epidemics that resulted in countless deaths. By the early twentieth century, cholera had been confined mostly to Asia. In 1961, however, a cholera pandemic beginning in Indonesia spread to Africa, the Mediterranean nations, and North America. Because cholera has a 50 to 60 percent fatality rate when its symptoms are not treated quickly, occasional cases cannot be ignored; both the consequences to afflicted people and the potential for the outbreak of epidemics are great.

Risk Factors

In the poorer nations of the world, cholera is still widespread and occurs where sanitation is inadequate. In the United States and other industrialized nations, where sanitation is generally good, only a few cases occur each year. These usually result from the return of afflicted travelers from regions where cholera is endemic. Several biological factors increase one's risk of contracting cholera: blood type O, female gender, and retinol deficiency. Furthermore, research has found that within the same household, first-degree relatives (offspring, parents, and siblings) have a greater chance of contracting cholera than second-degree relatives (aunts, grandchildren, grandparents, and uncles).

Etiology and Genetics

The disease occurs when cholera toxin binds to intestinal cells and stimulates the passage of water from the blood into the intestine. This water depletion and resultant cardiovascular collapse are major causes of cholera mortality. Study of the genetics and the biochemistry of cholera has shown that the toxin is a protein composed of portions called A and B subunits, each produced by a separate gene. When a bacterium secretes a molecule of cholera toxin, it binds to a cell of the intestinal lining (an intestinal mucosa cell) via B subunits. Then the A subunits cause the mucosal cell to stimulate the secretion of water and salts from the blood to produce diarrhea. Lesser amounts of the watery mix are vomited and exacerbate dehydration.

The use of bacterial genetics to compare virulent V. cholerae and strains that did not cause the disease helped in the discovery of the nature of the cholera toxin and enabled production of vaccines against the protein. These vaccines are useful to those individuals who visit areas where cholera is endemic, ensuring that they do not become infected with it during these travels. Unfortunately, the vaccines are effective only for about six months.

The basis for the operation of cholera toxin is production of a hormone substance called cyclic adenosine monophosphate (cAMP). The presence of excess in intestinal mucosa cells causes movement of water and other tissue components into the intestine and then out of the body. The accumulation of cAMP is caused by the ability of the cholera toxin to modify an protein, adenyl cyclase, to make it produce excess cAMP via modification of a control substance called a G-protein. This modification, called adenine ribosylation, is a mechanism similar to that causing diphtheria, another dangerous disease that can be fatal, although in diphtheria other tissues and processes are affected.

Seven cholera pandemics have occurred since 1817. Researchers have found that several biotypes have been responsible for these pandemics. The first five, which occurred from 1817 to 1896, were caused by the O1 classical biotype. The sixth pandemic, 1899 to 1923, was caused by the O1 classical biotype CTX^cla. Outbreaks from 1923 to 1961, which were sporadic, were found to be of the El Tor biotype. The seventh pandemic began in Indonesia in 1961 and spread to South Asia, Africa, and South America before it reached the Caribbean in 2010. It was also caused by the El Tor biotype.

Symptoms

Infection is almost always caused by consumption of food or water contaminated with the bacterium. It is followed in one to five days by watery diarrhea that may be accompanied by vomiting. The diarrhea and vomiting may cause the loss of as much as a pint of body water per hour. This fluid loss depletes the blood water and other tissues so severely that, if left unchecked, it can cause death within a day.

Screening and Diagnosis

The signs and symptoms of cholera are usually evident in areas where the disease is endemic. However, the only way to confirm this diagnosis is to test a patient’s stool sample for V. cholerae. Health care providers in remote parts of the world conduct rapid cholera dipstick tests that enable them to confirm quickly if a patient has the disease. Polymerase chain reaction (PCR) assays or other genetic tests can also confirm a diagnosis.

Treatment and Therapy

Treatment of cholera combines oral or intravenous rehydration of afflicted individuals with saline-nutrient solutions and chemotherapy with antibiotics , especially tetracycline. The two-pronged therapy replaces lost body water and destroys all V. cholerae in infected individuals. Antibiotic prophylaxis, which destroys the bacteria, leads to the cessation of production of cholera toxin, the substance that causes diarrhea, vomiting, and death.

Prevention and Outcomes

Cholera has, for centuries, been a serious threat to humans throughout the world. During the twentieth century, its consequences to industrialized nations diminished significantly with the advent of sound sanitation practices that almost entirely prevented the entry of V. cholerae into the food and water supply. In poorer nations with less adequate sanitation, the disease flourishes and is still a severe threat.

It must be remembered that dealing with cholera occurs at three levels. The isolation and identification of cholera toxin, as well as development of current short-term cholera vaccines, were highly dependent on genetic methodology. Vaccine protects most travelers from the disease. However, wherever the disease afflicts individuals, its treatment depends solely upon rehydration and use of antibiotics. Finally, cholera prevention focuses solely on adequate sanitation. Medicine seeks to produce a long-lasting vaccine for treatment of cholera to enable prolonged immunization at least at the ten-year level of tetanus shots. Efforts aimed at this goal are ongoing and utilize to define more clearly why long-term vaccination has so far been unsuccessful. Particularly useful will be fine genetic sequence analysis and the use of followed by DNA fingerprinting.

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