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Attacking Salmonella
How the aggressive bacteria use molecular staples to get inside your cells
Mention Salmonella and most people think bad eggs, raw chicken or dirty-handed short-order cooks.
Erec Stebbins thinks of staples.
Stebbins, whose Rockefeller University lab studies interactions between infectious microbes and the cells they invade, has discovered that the Salmonella bacterium penetrates cells and inflicts its gastrointestinal misery on one billion people each year via a protein in the remarkable shape of a staple.
The protein is called Salmonella invasion protein A, or SipA, and its method of action is beautiful in its simplicity. To fully understand how it works, Stebbins and first author Mirjana Lilic, along with colleagues from the University of Virginia, had to superimpose laboratory images of its molecular structure onto electron micrographs of it. They then processed the images on computers to tease apart the roles SipA plays in the invasion process.
The research, published in Science, found that while the Salmonella bacterium waits patiently outside, a “molecular syringe” injects SipA into the cell. Once inside, the middle core of the SipA protein – the backbone of the staple – binds to a cellular protein called actin in the host cell. Actin functions as a scaffolding protein that helps form the cell’s structure. The staple’s long arms then reach out and tether additional actin molecules to the first ones, forming a filament. This actin filament acts as a girder that begins to alter the shape of the cell’s membrane.
Eventually, the cell’s structural components have been reshaped to the point that the cell’s surface begins to expand and billow like a curtain. When enough extra folds have formed, the bacterium is enveloped in them and enters the cell (see illustration, below). The bacterium then turns off SipA and uses the cell’s protected, nutrient-rich environment to hide from the body’s immune system and fuel its replication.
“No protein in our cells is quite as potent, and elegant, as SipA,” says Stebbins, head of Rockefeller’s Laboratory of Structural Microbiology. “It’s able to go into a host cell, hijack the cell’s biochemistry and rearrange its structure. That’s a powerful example of host-pathogen co-evolution.”
And a successful one. Worldwide, Salmonella bacteria cause more than three million deaths each year, most of which are the result of contaminated food. (Salmonella has also been used as a biological weapon.) Stebbins’ research could also prove applicable to other pathogens.
“While SipA is specific to Salmonella, bacteria ranging from plant pathogens to the plague share a virulence system that is quite similar to the one Salmonella uses to gain entry into cells. What we have learned about Salmonella is a first step in a coming molecular understanding of similar processes in many bacteria,” Stebbins says.
Defining how pathogens get inside human cells may ultimately aid in the design of new antibiotics, an increasingly urgent need in the era of antibiotic resistance.

September 25, 2003



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