How the aggressive bacteria use molecular staples to get inside your cells
BY RENEE TWOMBLY
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
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
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
“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.