Mice Are Teaching Us How to Beat UTIs
Scientists have new clues to why some urinary tract infections (UTIs) recur persistently after multiple rounds of treatment
Working with mice, researchers at the Washington University School of Medicine, St. Louis, found that bacteria causing UTIs co-op a cell waste disposal - autophagy - system normally designed to help fight invaders. When the disposal system is disabled, the mice clear 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 work is published in the June 18, 2012, 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 led Mysorekar and her colleagues to speculate that E. coli cause recurrent urinary tract infections and may hide in garbage-bin-like vesicles - autophagosomes - within the cells lining the urinary tract.
Autophagosomes, found in nearly all cells, absorb harmful bacteria and worn-out cell parts from within the cell. They then merge with other cell vesicles filled with enzymes in order to dissolve this debris.
"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 who had developed mice with impaired or missing copies of an important autophagy gene, Atg16L1. Co-author Herbert W. Virgin, MD, PhD, and Edward Mallinckrodt, Head of the Department of Pathology and Immunology, along with their laboratory associates, created the mice to study Crohn's disease, a chronic bowel inflammation associated with mutations in Atg16L1.
The modified Atg16L1 mice were first infected with E. coli. Researchers then measured their urinary tract bacteria levels and found these levels decreased much more rapidly after infection than in normal mice. Cells lining the urinary tract in mice with the Atg16L1 mutation also had significantly fewer dormant reservoirs of E. coli than normal mice.
The scientists identified structural changes in urinary tract cells of the mice with the Atg16L1 mutation, which may help explain these unexpected results. The altered Atg16L1 gene is also associated with changes to the immune system. In the modified mice, E. coli infections in the urinary tract lead to more inflammatory immune factors being produced, which attracts additional bacteria-fighting immune cells to the infection site.
"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 Dr. 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 believes. "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 continue investigating how E. coli takes advantage of a fully functioning autophagy system in mice with urinary tract infections.
Wang C, Mendonsa GR, Symington JW, Zhang Q, Cadwell K, Virgin HW, Mysorekar IU. Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo. The Proceedings of the National Academy of Sciences, early online edition, week of June 18, 2012.
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.
Original article: https://news.wustl.edu/news/Pages/23982.aspx