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June 27, 2011
Key Step Identified in Legionnaires’ Infection
Researchers have uncovered a key step in how the bacterium responsible for Legionnaires’ disease takes control of the cells it infects. The finding may one day lead to new ways to treat Legionnaires’ disease and conditions caused by related bacteria.
Legionnaires’ disease is a form of pneumonia caused by Legionella bacteria. The disease was named after its discovery in a group of people attending an American Legion convention in 1976. Legionella bacteria live in fresh water and are often found in hot tubs, air conditioning cooling units and fountains. They cause disease when people inhale droplets of water containing the bacteria. People of all ages can get Legionnaires’ disease, but it primarily affects people with weakened or compromised immune systems, including those who are over age 65, those with lung disease and smokers.
The infection process in the lungs begins when Legionella bacteria are engulfed by immune cells known as macrophages. Macrophages patrol the lungs for potential disease-causing organisms and envelop them in balloon-like structures known as phagosomes. Ordinarily, foreign organisms are held inside phagosomes until they are destroyed. But Legionella hide out inside phagosomes and reproduce. Eventually, they manage to escape their host cell and infect other macrophages.
Previous studies have shown that Legionella bacteria force the cell to camouflage the phagosome by hijacking a cell protein called Rab1. The bacteria produce an enzyme that chemically changes Rab1, adding a molecule known as adenosine monophosphate (AMP). The AMP essentially jams the Rab1 switch into the “on” position. The activated Rab1 rests on the surface of the phagosome, serving as a kind of beacon that attracts bubble-like structures known as transport vesicles. These vesicles ordinarily ferry proteins around the cell. The vesicles eventually cover the phagosome and fuse with its membrane, hiding it from the cell’s defenses.
The bacterial signal that jams the Rab1 switch has been identified, but not the one that turns Rab1 off once the disguise is complete, allowing the bacteria to move on to the next stage of infection. A team led by Dr. Matthias P. Machner at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) sought to find out how Legionella bacteria turn off the jammed Rab1 switch.
The researchers searched the bacteria’s genome for clues. Genes for functionally linked proteins tend to be clustered together in bacterial genomes, so the scientists looked near the gene that encodes for the enzyme that helps to jam the Rab1 switch. In the advanced online edition of Science on June 16, 2011, they reported finding a nearby gene encoding a protein called SidD, whose function was unknown. A series of experiments revealed that SidD slices AMP from Rab1, which stops it from summoning vesicles to the phagosome.
“SidD switches off Rab1 when the bacterium no longer needs it,” Machner explains.
This finding may ultimately lead to new approaches for treating Legionella infections. It could also have implications for treating other disease-causing bacteria that use the strategy of adding AMP to host cell proteins. These include Vibrio parahemolyticus, which can contaminate seafood and cause food poisoning, and Haemophilus somni, which can cause a blood infection in cattle.