Exposing salmonella's gutsy moves.

Over thousands of years, bacteria have evolved many ingenious ways to invade the human body. Of all these microorganisms, strains of rod-shaped Salmonella have probably intrigued and befuddled scientists the most.

Best known for causing food poisoning and typhoid fever, Salmonella bacteria invade the cells that line the intestines. Amazingly, they seem to do this with the unwilling cooperation of the besieged cells. Under an electron microscope, the bacteria can be seen pressing up against an intestinal cell's microvilli -- tiny, fingerlike structures that stick out of the cell membrane. Soon these microvilli disappear and tiny blisters spring up in their place, engulfing the bacterial invaders. After two hours, the intestinal cell begins to look normal again. But the vanished bacteria are now inside.

Although researchers have watched Salmonella subvert intestinal cells for many years, nobody has understood how the microbes do it. But in the June 18 NATURE, scientists from the State University of New York at Stony Brook report finding the first clue: The bacteria use one of the cell's surface receptors to start the process.

In experiments with cultured intestinal cells, microbiologist Jorge E. Galan and his co-workers discovered that Salmonella typhimurium binds with receptors for epidermal growth factor (EGF) on the intestinal cell. Once bound, the receptor undergoes a chemical reaction called tyrosine phosphorylation, which sparks a number of changes in the intestinal cell. Eventually, these changes allow the bacteria to enter. When the researchers created a mutant S. typhimurium that could latch on to but no longer enter an intestinal cell, they found that the tyrosine phosphorylation reaction didn't occur. But when they added EGF to these mutants, the reaction took place and the mutants invaded the intestinal cell.

How does S. typhimurium bind to the receptor for EGF? Galan thinks it may have an EGF look-alike molecule that acts as a passkey. On the other hand, notes microbiologist Daniel A. Portnoy of the University of Pennsylvania in Philadelphia, the EGF receptor is very complex, so the bacteria may use other, more complicated devices to accomplish its goal.

The big question, says Portnoy, is how Salmonella manages to coerce intestinal cells into ingesting it. While some body cells, such as white blood cells, regularly engulf and ingest particles from their surroundings, intestinal cells do not, he says.

Galan thinks the answer lies with the cell's internal architecture. Each microvillus contains 20 structures called microfilaments, which function much like the poles supporting a tent. These tiny rods give the microvilli their shape and keep the cell membrane taut.

During tyrosine phosphorylation, however, calcium levels increase inside the intestinal cell. Galan thinks the abundant calcium eventually dissolves the bonds that hold the microfilaments together. As the rods come apart, the cell membrane becomes slack and allows microvilli to swell into the blisters seen during Salmonella invasion.

Once scientists discover how these bacteria bind to the EGF receptor, they may be able to develop a vaccine to thwart them, says Portnoy. In the meantime, studies of Salmonella should provide insights into cell communication and microbial hijacking. "This area of host-parasite interaction at the molecular level is really very new," Portnoy says.

Moreover, says Galan, "bacteria are becoming a wonderful tool to learn more about fundamental aspects of cell biology."