Cholera hides sinister stowaway.

Cholera has come nearly full circle, again. Beginning in Indonesia in 1961, the tireless traveler has almost completed its seventh circumnavigation of the globe since 1817, leaving freshly dug graves as evidence of its passage. In Latin America alone, cholera has claimed more than 10,000 lives since its landfall in Peru less than 6 years ago.

Now, scientists trying to determine what makes Vibrio cholerae so deadly and unstoppable have discovered that the virulent bacterium does not travel alone.

Deep inside it resides a viral stowaway packing all the genes needed to turn even harmless strains of cholera into killers.

The virus-known as a bacteriophage, or phage-leaps readily from one cholera strain to the next, a capability that had been postulated for phages but never demonstrated before in the laboratory or in nature.

The cholera-infecting phage attaches itself to slender receptors called pili, which, in the human intestine, bristle from the cholera bacterium like a bad haircut. The phage then slips into the bacterium and deposits into its chromosome a tidy package of genes that code for cholera toxin. Without these genes, the bacterium is harmless.

"We are a hospitable environment for the infection of Vibrio by phage," says Matthew K. Waldor of the Tupper Research Institute of New England Medical Center in Boston, who, with John J. Mekalanos of Harvard Medical School's Shipley Institute of Medicine, reported the finding in the June 28 Science.

Waldor and Mekalanos began by removing cholera toxin genes from the prevalent El Tor strain and substituting genes that confer resistance to antibiotics.

They showed that a phage carried the resistance genes as it moved from the infected strain to a strain that lacked the virulence genes. In this experiment, the gene that usually switches on toxin production conferred resistance instead.

Under favorable conditions, each phage with resistance genes infected millions of cholera bacteria. If conditions were changed so that the bacteria didn't produce pili, the transfer didn't take place at all.

"That's the proof that the pili are the receptors for the phage," says Stephen Richardson of the Bowman Gray School of Medicine at Wake Forest University in Winston-Salem, N.C.

Scientists say the work clarifies why some cholera bacteria cause disease while others of the same strain do not. It also promises to open new avenues of study into the virulence factors of other microorganisms (SN: 12/2/95, p.383).

The findings have also disclosed a hidden pitfall of efforts to develop a live cholera vaccine. Phages may infect the deliberately weakened vaccine bacterium, turning it into a microbial Trojan horse full of cholera toxin.

In a sense, the work also brings bacteriophage research full circle, to the era when phage discoverer Felix d'Herelle of the Pasteur Institute in Paris thought he could use these viruses to cure cholera (SN: 6/1/96, p. 350). Soon after d'Herelle reported his find in 1917, he began following cholera around the globe, trying to mitigate its impact.

He was unable to improve upon the accomplishment of physician John Snow, who in 1856 traced an outbreak of cholera in London to an area surrounding a communal pump. Removing the pump handle, Snow ended the epidemic, proved that cholera is waterborne, and inspired the preventive strategy used successfully today in the United States and other developed nations.

D'Herelle's phage work, however, provided the basis for the new findings, which may help scientists prevent future pandemics. "They certainly could lead to some interesting approaches to breaking the infectious cycle," Richardson says.