Researchers at Washington University and Stanford University have captured time-lapse movies of a urinary tract infection 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 percent 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, published in 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.
At other points in the infection, 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,” said 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.”
Scientists estimate half of all women will experience a UTI, the second-most common type of bacterial infection, at some point in their lives, and additional recurrent UTIs will affect 20 percent 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, researchers in 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 said. “Some kind of switch occurs, and instead of acting like individual bacteria, they behave more in a multicellular manner, working together to defeat the cell’s defenses.”
Hultgren and his co-authors 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.
In the third stage, bacteria begin to break out of the IBC and swim away.
“It’s like peeling an onion,” said 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 that may help them evade the immune system.
The movies also reveal that groups of E. coli will sometimes shift into an inactive or quiescent state, possibly providing a seed for recurrent infection.
Researchers in Hultgren’s lab are working to better understand the distinctions between the various stages of development.
“There’s such complex genetic circuitry involved here that we’re going to have to start thinking about this like electrical engineers,” Hultgren said. “But the more we can understand this network, the better our chances of figuring out ways to interrupt it.”