Talk about a low-down, dirty trick. New research reveals that bacteria deploy duplicates of human proteins to jam our body's early warning system. The results might lead to improved treatments for bacterial infections and for diseases such as arthritis that are caused by an overactive immune system.
Any good military defense employs radar, and our immune system is no exception. Immune cells known as macrophages and dendritic cells carry so-called Toll-like receptors, which raise the alarm if they detect bits of bacterial membrane or other telltale signs of microbial invasion. A portion of the Toll-like receptor called the TIR domain transmits the warning signal to another protein called MyD88, which passes it on to other molecules. The end result is the release of chemicals such as tumor necrosis factor (TNF) that summon infection-fighting cells.
Microbes have devised a few ways to escape detection. Two years ago, for example, researchers found that Salmonella bacteria manufacture proteins that are dead ringers for the TIR domain and that short-circuit the Toll-like alarm system. However, scientists didn't know how widespread this countermeasure was.
To find out, immunologist Thomas Miethke of the Technical University of Munich in Germany and colleagues scanned bacterial genome databases for genes that encode TIR-like proteins. The team reports online this week in Nature Medicine that it has identified these mimics in several bugs, including a strain of the intestinal bacterium Escherichia coli that can trigger urinary infections, and in a penicillin-resistant strain of Staphylococcus aureus. The proteins gave the bacteria an edge. E. coli that produce TIR mimics triggered more severe kidney infections in mice than did bacteria lacking the proteins. Likewise, in patients with E. coli-induced urinary tract infections, the more serious the illness, the more likely the microbes were copying human TIR.
What's going on? The fake TIRs act as decoys, the researchers report. They latch onto MyD88 and prevent it from receiving the alarm signal from the Toll-like receptors, but they don't alert immune cells. A drug that shut down the bacteria's ability to secrete these copycat proteins restored normal TNF release from macrophages in the culture dish, suggesting that it might prove effective against some infections.
"I think it's a great piece of work," says immunologist Bruce Beutler of the Scripps Research Institute in San Diego, California. The finding could have therapeutic benefits beyond fighting bugs, adds immunologist Luke O'Neill of Trinity College Dublin in the U.K. He notes that the copycat proteins might help researchers design drugs to quell autoimmune diseases such as arthritis and lupus, in which hyperactive Toll-like receptors provoke immune attacks on the body's own tissues.