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| women-health-info.com |
Researchers
at Washington University School of Medicine in St. Louis and Stanford
University have captured time-lapse movies of a urinary tract
infection (UTI) in progress, illuminating several new details of how
the bacteria E. coli invade cells and gang up to overwhelm the cells'
defenses.
The
images reveal for the first time that E. coli, which are responsible
for 80 to 90 percent of all UTIs, pass through at least four distinct
developmental stages during the course of an infection. Researchers
hope to further define these stages and use them as guides in the
search for new drugs.
The
study, to be published this week in the early online edition of the
Proceedings of the National Academy of Sciences, also reveals that
bacteria will sometimes shift into an inactive state, creating
reservoirs of infection within the bladder that might be responsible
for some of the recurrent UTIs that plague many women.
To
image the bacteria in action through a videomicroscope, researchers
made the bacteria glow by adding a phosphorescent green protein. The
movies show the bacteria rapidly changing themselves and their
interactions with each other to collectively hijack bladder cells and
use them as safe havens for replication.
"It
just boggles the mind what these bacteria can do, in terms of sensing
and responding to their environment and each other," says Scott
J. Hultgren, Ph.D., the Helen Lehbrink Stoever Professor of Molecular
Microbiology and lead investigator of the study. "This has never
been seen before in live host tissue, and parts of this process are
probably present in a multitude of different kinds of pathogens."
UTIs,
which mainly occur in women, are the second most common type of
bacterial infection. Linked to poor hygiene, sexual behavior and
migration of intestinal flora, they are believed to cause around $1.6
billion in medical expenses every year in the United States.
Scientists estimate half of all women will experience a UTI at some
point in their lives, and additional recurrent UTIs will affect 20 to
40 percent of these patients.
Clinicians
had assumed that E. coli and other bacteria that cause UTIs were not
invading cells of the urinary tract, but in June 2003, Hultgren's lab
produced images of E. coli forming biofilms inside bladder cells.
Biofilms are networks of single-celled pathogens that cooperate with
each other to form structures that are resistant to attack.
"Once
these bacteria begin to replicate inside their target cell, they
almost behave more like a multicellular organism," Hultgren
explains. "Some kind of switch occurs, probably due to
processing of environmental cues, and instead of acting like
individual bacteria, they behave more in a multicellular manner,
working together to defeat the cell's defenses."
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| women-health-info.com |
Hultgren
and his coauthors divided E. coli's infectious process into four
stages. In the first, bacteria enter bladder cells and begin
replicating rapidly. In the second stage, they decrease their size
and replication rate and begin to form the intracellular bacterial
community (IBC), a podlike structure that Hultgren compared to a
marble in a balloon.
In
the third stage, bacteria begin to break out of the IBC and swim
away. "It's
like peeling an onion," says Sheryl S. Justice, Ph.D., a
postdoctoral fellow in Hultgren's lab and one of three lead authors
of the paper. "They come off the outside of the IBC in
successive layers."
During
the fourth stage, some of the bacteria from the dispersed IBC become
filaments, taking on long, thin, needle-like shapes. The new shapes
may help them evade the immune system and seek chances to start new
infections both in the urinary tract of their hosts and in new hosts.
The
movies also reveal that groups of E. coli will sometimes shift into
an inactive or quiescent state. "We don't actually know when
this happens, but at some point, that's all you see -- small numbers
of bacteria inside the cells no longer replicating," Hultgren
says. "They've entered this quiescent state and are presumably
no longer causing any symptoms, and the question is whether that
quiescent reservoir can now provide seeds for recurrent infections."
Hultgren's
lab is working to better understand the distinctions between the
various stages of development, including the signals that trigger the
changes from one stage to the next.
"There's
such complex genetic circuitry involved here that we're going to have
to start thinking about this like electrical engineers,"
Hultgren says. "But the more we can understand this network, the
better our chances of figuring out ways to interrupt it."
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