Researchers in California have shown that removing or inactivating a key gene can disarm bacteria and prevent it from starting an infection. The discovery, reported in the journal Science, could lead to powerful new vaccines and antibiotics.
Dr. Michael Mahan of the University of California, Santa Barbara, leader of the team that made the discovery, said the work shows how salmonella bacteria, a major source of food poisoning in humans, causes illness.
"We've uncovered a genetic master switch that controls bacterial infection," said Mahan. "When we knock out this switch, the bacterium is completely disabled in its ability to cause disease."
Mahan said the DAM genenamed for for DNA adenine methylasewas found after a five-year process of examining bacterial genes that are turned on at the start of an infection in a host animal. Often these genes are quiet in laboratory dishes and go into action only when the pathogen is starting an infection inside an animal.
"Bacterial pathogens act like a Trojan horsethey hide their weapons until they are within an animal," said Mahan. As a result, some bacterial genes that cause infection "are turned on inside a mouse and off outside a mouse," he said.
The UCSB researchers found that the salmonella DAM gene makes a protein that activates other genes to start a biological cascade that leads to infection. When strains of salmonella were created that contained a permanently disabled DAM gene, the microbe could not cause disease in mice. The altered bacteria also acted like a vaccine, causing the mouse's immune system to make antibodies that would attack salmonella, said Mahan.
"Mice immunized with this crippled strain of salmonella were completely protected from infection," he said. Seventeen of the immunized mice were injected with a salmonella dose 10,000 times more powerful than a dose that is lethal to half of all mice. All of the experimental animals survived. Another 12 mice that had not been immunized died after a thousand-fold lower exposure.
A variety of other bacteria pathogens, including cholera, E. Coli and Shigella dysentery, also have DAM genes, raising the possibility that those diseases could also be disabled by blocking DAM. Mahan said it may be possible to make an antibiotic based on the DAM gene. If a chemical could be found that blocks the action of the protein made by DAM, then it might prevent bacteria from continuing the infection process.
Mahan and colleagues say they are in the final stages of setting up a new biotechnology company aimed at using this genetic switch to create vaccines and treatments for infectious diseases, something that is critical now because of the growing problem of bacteria that have become resistant to the best medicines available to fight them.