Gene Promises Route to Potent Vaccines

Scientists have found a remarkable gene that may lead to a whole new generation of vaccines and antibiotics. In this week's issue of Science, researchers describe a gene in Salmonella bacteria that, like a master switch, turns on a range of other genes needed for infection. Bacteria stripped of the gene are harmless to mice but make an excellent vaccine.

Pathogens have many so-called "virulence genes," which are switched off when the bacteria are living on a petri dish or a chicken in the refrigerator, but spring into action once they enter the gut of a mammal. A team led by geneticist Michael Mahan at the University of California, Santa Barbara, had already discovered some 250 of these genes in Salmonella typhimurium, which causes food poisoning in humans and a typhoidlike disease in mice.

In search of a single gene that could turn many virulence genes on and off, the researchers turned their attention to DNA adenine methylase (Dam), an enzyme that plays a role in DNA repair and is known to be necessary for infection in Escherichia coli strains that cause urinary tract infections. To see whether Dam might play a wider role, the team created an S. typhimurium strain that lacked the dam gene. When given orally to mice, the bacteria proved utterly innocuous: They entered the gut lining but didn't cause a major infection. Measurements of gene activity showed that the absence of Dam had altered the expression of at least 20 virulence genes.

Drugs that block Dam could slow bacterial growth and possibly offer a whole new generation of antibiotics, says Mahan. Also exciting is the possible use of Dam-stripped bacteria as a vaccine. When the team immunized 17 mice with Dam-negative S. typhimurium, the animals were immune to the normal bacterium 5 weeks later; they could withstand doses of up to 10,000 times the amount that killed nonimmunized mice.

The findings could lead to animal vaccines that help eradicate Salmonella from the food chain. Other diseases could also become targets. Because genetic studies have shown that the bacteria that cause cholera, meningitis, plague, dysentery, and syphilis all have dam, perhaps they too can be crippled by knocking out the dam gene. "On the heels of this paper, a variety of labs will probably quickly knock out [dam] in their individual bugs," predicts microbiologist John Mekalanos of Harvard Medical School in Boston.