How Cholera Became a Killer

By Josie Glausiusz|Tuesday, October 01, 1996
RELATED TAGS: INFECTIOUS DISEASES
In 1961 a cholera pandemic broke out in Indonesia. Within five years the disease spread to India, the Soviet Union, Iran, and Iraq, within ten to West Africa. By 1991 it had struck Latin America. In 1995 alone, the disease killed more than 5,000 people worldwide and sickened hundreds of thousands more with debilitating diarrhea.

Just one strain of the bacterial species Vibrio cholerae wreaked almost all the death and misery. This strain is known as O1, and it produces a toxin that binds to cells of the small intestine, setting off a cascade of reactions in which cells pump out vast amounts of chloride ions and water--some five gallons a day. If salts and water are not quickly replaced, the patient dies.

Surprisingly, most strains of V. cholerae are harmless organisms that live and multiply in rivers and the open sea. But at some time in its evolutionary history, the O1 strain turned lethal. What caused this deadly transformation? A virus, according to microbiologist Matthew Waldor.

Waldor, who works at the New England Medical Center in Boston, and his colleague John Mekalanos at Harvard discovered the virus while studying the stretch of bacterial dna known to include the gene, called ctx, that codes for the cholera toxin. They suspected that a virus might have infected the bacteria with the gene, since viruses often insert their own genetic material into bacteria. Another possibility was that different strains of bacteria were swapping genes, a routine occurrence among wild strains.

Waldor and Mekalanos found that a virus was indeed the culprit after taking O1 bacteria and replacing the toxin gene with one coding for resistance to an antibiotic. They then cultured these bacteria with an antibiotic-susceptible strain and found that some of the second bacteria had now become resistant.

They next passed the bacteria through a very fine filter. The bacteria-free fluid left behind could still transfer antibiotic resistance, even when treated with an enzyme that attacks naked dna--that is, dna not sheltered by the protein coat that protects a virus. Waldor and Mekalanos concluded that a virus was ferrying the gene from one strain to another; using an electron microscope, they succeeded in photographing it.

The researchers suspect the long, stringy virus enters bacteria via their pili--hairlike structures the bacteria use to stick to the gut. The pili are suspect because bacteria that lack them resist infection. By invading bacteria, the ctx virus gains a home; in addition, its genes are copied every time bacteria divide. Is Vibrio, then, merely the victim of merciless parasitism? Apparently not. The watery, salty diarrhea induced by the toxin, says Waldor, gives the bacteria a perfect medium in which to grow. For the cholera bacterium, it’s like Miami Beach, says Waldor. It’s just a fine place to be. So fine, in fact, that each thousandth of a quart of diarrhea, of some 20 quarts produced daily, contains about 100 million bacteria. If the cholera victim defecates in a river, he helps the bacteria--and the virus--spread.

Although ctx is not the first virus known to induce disease in this way--diphtheria and botulism are both caused by virally hijacked bacteria--its discovery could lead to a safer live cholera vaccine. One recently developed vaccine contains V. cholerae with a partially deleted toxin gene. It has been tested in 6,500 people around the world and appears to be safe and highly protective. Nevertheless, there is always the danger that a vaccine bacterium inside the body could be reinfected by a ctx virus.

Waldor and Mekalanos think their vaccine will avoid that risk. In our vaccine, we’ve deleted the attachment site on the bacteria for the virus, so the virus can’t enter the chromosome, says Waldor. Deprived of its home, the virus cannot survive for long. Waldor and Mekalanos’s vaccine has been tested in about 100 Army volunteers with no resulting illness. Trials over the next two years should determine how effective their vaccine really is.
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