Their research, conducted in mice, suggests that the bacteria that cause urinary tract infections take advantage of a cellular waste disposal system that normally helps fight invaders. In a counterintuitive finding, they learned that when the disposal system was disabled, the mice cleared urinary tract infections much more quickly and thoroughly.
"This could be the beginning of a paradigm shift in how we think about the relationship between this waste disposal system, known as autophagy, and disease-causing organisms," says senior author Indira Mysorekar, PhD, assistant professor of obstetrics and gynecology and of pathology and immunology. "There may be other persistent pathogens that have found ways to exploit autophagy, and that information will be very useful for identifying new treatments."
The results will be published the week of June 18, 2012, in the early online edition of The Proceedings of the National Academy of the Sciences.
Urinary tract infections are very common, particularly in women. In the United States alone, annual treatment costs are estimated to run as high as $1.6 billion. Scientists believe 80 percent to 90 percent of these infections are caused by the bacterium Escherichia coli (E. coli).
Data from the new study and earlier results have led Mysorekar and her colleagues to speculate that E. coli that cause recurrent urinary tract infections may hide in garbage-bin-like compartments within the cells that line the urinary tract.
These compartments, found in nearly all cells, are called autophagosomes. They sweep up debris within the cell, including harmful bacteria and worn-out cell parts. Then, they merge with other compartments in the cell that are filled with enzymes that break down the contents of autophagosomes.
"We think, but can't yet prove, that the bacteria have found a way to block this final step, " Myosrekar says. "This would transform the autophagosome from a death trap into a safe haven where the bacteria can wait, hidden from the immune system, for their next chance to start an infection."
In the new research, Mysorekar teamed with colleagues at the School of Medicine who had developed mice in which both copies of an important autophagy gene, Atg16L1, were impaired. Co-author Herbert W. Virgin, MD, PhD, Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology, and others created the mice to study Crohn's disease, a chronic bowel inflammation associated with mutations in Atg16L1.
Co-lead authors Caihong Wang, DVM, PhD, a staff scientist, and Jane Symington, an MD/PhD student in the Mysorekar group, infected the mice with E. coli. The researchers found that bacteria levels in the urinary tracts of the modified mice decreased much more rapidly after infection than they did in normal mice. Cells lining the urinary tract in mice with the mutated gene also had significantly fewer dormant reservoirs of E. coli than in normal mice.
The scientists identified structural changes in urinary tract cells of the mice with Atg16L1 mutations that may help explain their unexpected results. These changes may have made it much more difficult for the bacteria to find and break into autophagosomes, Mysorekar says.
The altered gene also was associated with changes in the immune system. In the modified mice, E. coli infections in the urinary tract led cells to produce more inflammatory immune factors and prompted additional bacteria-fighting immune cells to come to the site of the infection.
"The immune system appears to be primed to attack at the slightest provocation in the mice with mutations," Mysorekar says. "This may be why mutations in Atg16L1 are also connected with Crohn's disease, which involves immune cells erroneously attacking beneficial microorganisms in the gut."
Mutations in Atg16L1 are quite common, according to Virgin, although not everyone who has a mutated form of the gene will get Crohn's disease.
"These new results may help explain why the mutations have persisted for so long in the general population," he says. "They don't just put the carrier at risk of Crohn's disease, they also may have a protective effect that helps fight infections."Mysorekar plans to investigate how E. coli takes advantage of a fully functioning autophagy system in mice with urinary tract infections.
Funding from National Institute of Child Health and Human Development Grant T32-54560 (to G.R.M.), U54AI057160, Project 5 (to H.W.V.) and K99/R00 Pathway to Independence Award DK080643 (to I.U.M.) supported this research.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Michael C. Purdy | EurekAlert!
Antibiotic effective against drug-resistant bacteria in pediatric skin infections
17.02.2017 | University of California - San Diego
Tiny magnetic implant offers new drug delivery method
14.02.2017 | University of British Columbia
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
17.02.2017 | Medical Engineering
17.02.2017 | Medical Engineering
17.02.2017 | Health and Medicine