Study describes how E. coli co-opts cells, causes recurrent UTIsAug. 25, 2022, 9:37 AM
by Bill Snyder
Researchers at Vanderbilt University Medical Center have discovered why the uropathogenic bacterium Escherichia coli (E. coli), the leading cause of urinary tract infections, is so tenacious.
Their findings, published this week in the journal Nature Microbiology, could lead to the development of new ways to prevent recurrent UTIs by blocking bacterial colonization and the formation of persistent E. coli “reservoirs” in the bladder.
“During UTI, bacteria co-opt the bladder cell, turning it into a bacterial factory, in which they multiply in numbers,” said the paper’s corresponding author, Maria Hadjifrangiskou, PhD, associate professor of Pathology, Microbiology & Immunology and Urology at VUMC.
“In this work, we figure out how bacteria accomplish this, opening new avenues for discovery, as well as pathways for new therapeutic development,” she said.
Each year UTIs afflict an estimated 150 million people worldwide. While most UTIs are easily treated with antibiotics, repeated infections can occur if the bacterium develops drug resistance.
In their investigation, the VUMC researchers focused on cytochrome bd, an enzyme E. coli uses to scavenge and use oxygen as its metabolic power source to grow and spread.
By combining bacterial genetics with cell culture and mouse models of infection, they demonstrated that E. coli requires cytochrome bd to infect the urothelial cells lining the urinary tract.
Through a series of genetic, biochemical, and functional assays, they showed that the oxygen-scavenging enzyme saps the supply of oxygen needed by mitochondria, which generates the chemical energy used by most cells in the body through a process known as mitochondrial respiration.
Not only does the enzyme reduce the efficiency of mitochondrial respiration, but it also stabilizes HIF-1, a hypoxia-inducible transcription factor that enables E. coli to thrive under low-oxygen conditions, the researchers found.
This bacteria-induced “subversion” and “rewiring” of mitochondrial metabolism prevents the normal turnover of urothelial cells, thereby preserving a replicative “niche” for continued growth of the bacterium and facilitating its persistence in the urinary tract.
The study identifies potential targets for impeding bacterial virulence in the bladder. Among them: inhibition of cytochrome bd, pharmacologic modulation of HIF-1 activity, and agents that promote the normal death and turnover of urothelial cells, a process known as apoptosis.
Connor Beebout, PhD, an MD/PhD student in Hadjifrangiskou’s lab, is the paper’s first author.
Hadjifrangiskou said the work would not have been possible without the “amazing collaboration” of VUMC faculty co-authors Walter Chazin, PhD, Vivian Gama, PhD, Kimryn Rathmell, MD, PhD, and Jeffrey Rathmell, PhD, and their colleagues.
Other co-authors are Gabriella Robertson, Bradley Reinfeld, PhD, Alexandra Blee, PhD, Grace Morales, and John Brannon, PhD.
This work was supported by National Institutes of Health grants AI150077, GM007347, NS125829, CA247202, CA250258, AI112541, GM007569, AI127793, AI101171, DK105550, GM128915, MH123971, AI107052, and DK123967, and by a Howard Hughes Medical Institute Gilliam Fellowship.